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Unilateral glomerulonephritis
Unilateral Glomerulonephritis* Virtual Absence of Nephritis in a Kidney with Partial Occlusion of the Main Renal Artery JOHN M . PALMER, M .D ., STANTON L . EVERSOLE, M .D . and THOMAS A . STAMEY, M .D . Palo Alto, California
LOMERULONEPHRITIS has been accepted as a disease which always involves both kidneys [1] . However, we have recently studied a patient who seems to be an exception to this rule . This patient was hypertensive and had occlusive vascular disease in the left main renal artery . A left nephrectomy and a biopsy of the right kidney were performed . The biopsy specimen revealed a diffuse, proliferative glomerulonephritis which was not present in the left kidney .
G
CASE REPORT E .C . (No . 11-29-39), a fifty-seven year old Caucasian housewife, was first seen at the Stanford Medical Center on February 11, 1963, for evaluation of hypertension . She was known to be hypertensive since her only pregnancy fifteen years previously, but had received no therapy other than mild sedatives . In 1960 microscopic hematuria and proteinuria were noted for the first time . An intravenous pyelogram showed a left renal mass . Blood pressure readings ranged from 160/110 to 200/120 mm . Hg . Exploratory examination of the left kidney was performed at another hospital and a small renal cyst was found . The cyst was opened but a renal biopsy was not performed . In 1962 the patient was readmitted because of mild gastrointestinal complaints ; the blood pressure was 210/110 mm . Hg . Microscopic hematuria was again noted, with 2+ proteinuria . Cystoscopy and retrograde pyelograms failed to reveal the etiology of the microscopic hematuria. In October 1962 easy fatigability, cardiac palpitations and occasional dull precordial pain without radiation prompted the patient to seek medical advice . The blood pressure was 200/120 mm . Hg . Urinalysis revealed 4+ proteinuria with 40 to 50 red cells per high power field and occasional hyaline casts . Mild occipital headaches became more severe, and she was referred to the Stanford Medical Center. There was no history of streptococcal infection or
rheumatic fever. The patient had had typhoid fever at six years of age . Her mother had been hypertensive and died of a stroke at the age of seventy-three . On physical examination the patient was afebrile and in no acute distress . Moderate obesity was present. Blood pressure was 170/110 mm . Hg . Her peripheral vision was decreased and examination of the optic fundi revealed retinitis pigmentosa ; grade 1 hypertensive retinopathy was also present. The neck veins were flat. The lungs were clear to percussion and auscultation, and the heart was not enlarged on clinical examination . No cardiac murmurs were present . The right kidney was palpable . There were no abdominal bruits. The pedal pulses were decreased although palpable. The remainder of the examination was within normal limits .
LABORATORY STUDIES The hematocrit was 40 per cent, hemoglobin 14 .5 gm . per cent white blood cell count 10,700 per cu . mm, with a normal differential, and erythrocyte sedimentation rate 31 mm . per hour . Specific gravity of a random urine sample was 1 .013 ; there was 1+ proteinuria . Urinalysis for glucose was negative . Microscopic examination of the urinary sediment revealed 8 to 10 red cells and 1 to 3 white cells per high power field ; 1 granular cast was seen on the slide . No red cell casts were present on multiple urine examinations . Several urine cultures were sterile . The serum creatinine was 1 .2 mg . per cent, and the serum electrolytes were normal . A 24 hour urine protein determination showed 0 .54 gm . The antistreptolysin 0 titer was 166 Todd units ; this elevated titer was thought to be compatible with a previous streptococcal infection . Serum total protein was 7 .2 gm . per 100 ml . Serum protein electrophoresis showed 54 per cent albumin and 46 per cent globulin with 4 per cent alpha,, 13 per cent alpha2, 10 per cent
* From the Division of Urology and Surgical Pathology, Stanford University School of Medicine, Palo Alto, California . Manuscript received September 17, 1965 . 816
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et al .
817
FIG. 1 . A, an intravenous pyelogram ob a ned fi e months a er exploratory examination uc the e kidney for hematuria . There was a 1 .7 cm . difference in renal size . B, a retrograde pyelogram obtained three }ears after examination of the left kidney . The cortical margins are easily discernible ; there was uniform cortical atrophy and a 3 .2 cm. difference in renal size .
FIG . 2 . Rapid-sequence films (intravenous pyelogram) . A, I minute film . '1 'he nephrogram of the left kidney appears more dense . B, 2 minute film . The contrast medium had reached the calyces and pelves of both kidneys at the same time . C, 3 minute film . The calyces and pelvis of the left kidney appear smaller than the right, suggesting a decreased urine volume . D, 5 minute film . There is no evidence of hyperconcentration of the contrast medium in the left kidney .
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3B
FIG . 3 . A, transfemoral abdominal aortogram . There is marked stenosis of the left main renal artery near its ostium . The right renal artery and its branches are not obstructed . Severe arteriosclerotic involvement of the aorta is present and aneurysmal dilation is seen above the celiac axis . B, the severity of the stenosis in the left renal artery is emphasized by the left posterior oblique position .
beta and 19 per cent gamma globulins . A roentgenogram of the chest indicated normal lung fields and left ventricular enlargement ; the electrocardiogram demonstrated left axis deviation . Figure 1A is from an intravenous pyelogram obtained five months after the left renal exploration in 1960 . Figure 1B is from a retrograde pyelogram performed in 1963 ; a 1 .5 cm. decrease in left renal size is apparent . Although it is sometimes fallacious to compare a retrograde with an intravenous pyelogram, the renal shadows were well seen in each study and both series were made at the same radiologic unit . In March 1963 an intravenous pyelogram was obtained at Stanford . (Fig . 2 .) There was a prompt nephrogram bilaterally at 1 minute (Fig . 2A), seemingly more dense in the left kidney. By 2 minutes, contrast material had reached the collecting system of each kidney. (Fig . 2B .) Although there was no delay in excretion of contrast material by the left kidney and no clear-cut evidence of hyperconcentration on that side, there had been a striking decrease in left renal size since 1960 . Transfemoral arteriography demonstrated a localized stenotic obstruction of the left renal artery at its origin . (Fig . 3 .) There was fusiform aneurysmal dilation of the abdominal aorta just above the celiac axis, and extensive arteriosclerotic changes were present below the renal arteries . Differential renal function studies were performed (Table I) using an infusion of urea, saline solution and antidiuretic hormone (ADH) . There was a 10 :1 difference in urine flow rates
with a 280 per cent increase in the concentration of para-aminohippurate (PAH) in the left kidney . On March 15, 1964, the abdomen was explored . The blood pressure in the abdominal aorta was 138/96 mm . Hg ; the blood pressure in the renal artery distal to the obstruction was 108/86 mm . Hg . Because of the patient's age and the severe arteriosclerosis of the abdominal aorta, a left nephrectomy and a wedge biopsy of the right kidney were performed . The postoperative course was uneventful . The blood pressure did not change significantly . In the hospital prior to left nephrectomy it was 157/101 mm . Hg . (an average of seventy-seven readings) ; following surgery it was 153/99 mm . Hg (an average of seventy-four readings) . The remaining kidney was studied three times during the following two years ; an indwelling Foley catheter and oral water hydration were used for each study . (Table II .) The urine continued to show 20 to 40 red blood cells per high power field and 5 to 20 mg . of protein per 100 ml . The most recent urinalysis, performed on March 11, 1965, revealed 5 mg . of protein per 100 ml ., 10 to 40 red cells per high power field and 1 to 3 granular casts per low power field . The blood pressure was unchanged until the most recent visit when, one month after initiation of antihypertensive medication, it was 142/90 mm . Hg . PATHOLOGIC STUDIES
The left kidney weighed 100 gm . and the cortex measured less than 4 mm . in thickness . A dilated calyx beneath a small cortical scar at one pole of the kidney contained an impacted stone . AMERICAN JOURNAL O F MEDICINE
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TABLE I RESULTS OF PREOPERATIVE DIFFERENTIAL RENAL FUNCTION STUDY (MARCH 13, 1964)
`rime (min .)
--50 -41 -40 -31 -30 -28
Data
Blood pressure 192/122 mm . Hg Infusion of 8 % urea in normal saline solution started at 9 .6 ml./ min . t o deliver 1 .50 mg./ml . inulin, 1 .01 mg./ml . PAH and 5 mtJ ./kg ./ hr. ADH 21 .9 ml . 10% inulin and 2 .4 ml . 20% PAH injected intravenously 1 ml . 0 .25% heavy Nupercaine® injected into 4th lumbar interspace for saddle anesthesia 292 mU . ADH injected intravenously Blood pressure 190/130 mm . Hg No . 8 French polyethylene catheter passed to left mid-ureter No. 7 French polyethylene catheter passed to right mid-ureter Blood pressure 206/124 mm . Hg
% Filtered Na Excreted CNs ((CNa/Cln) X (ml./min .) 100)
Kidney
V (ml ./ min .)
Uia (mg./100 ml .)
Cl . (ml./min ./ 173 M2 .)
UPAB (mg./100 ml .)
14-24
Left Right Left/Right
2 .32 21 .68 0 .11
157 .1 68 .2 2 .30
18 71 0 .25
93 .3 31 .7 2 .94
83 264 0 .31
0 .22 0 .27 0 .81
95 .4 100 .4 0 .95
1 .64 16 .10 0 .10
24-34
Left Right Left/Right
2 .35 22 .20 0 .11
18 70 0 .26
83 .6 30 .7 2 .72
94 .1 99 .1 0 .95
Left Right Left/Right
2 .62 24 .00 0 .11
17 69 0 .25
73 .1 26 .9 2 .72
76 262 0 .29 74 248 0 .30
0 .24 0 .27 0 .89
34-44
155 .4 65 .6 2 .37 134 .9 60 .2 2 .24
0 .23 0 .28 0 .82
95 .1 99 .4 0 .96
1 .64 16 .27 0 .10 1 .84 17 .64 0 .10
14-44 (Av .)
Left Right Left/Right
2 .43 22 .63 0 .11
149 .1 64 .7 2 .30
18 70 0 .26
83 .3 29 .8 2 .80
78 258 0 .30
0 .23 0 .27 0 .85
94 .9 99 .6 0 .95
1 .71 16 .67 0 .10
Time (min .)
CPAE Filtration (ml./min / Fraction 173 MI .) (Cl n /CPAH)
UN. (mEq ./L .)
9 .1 22 .7 0 .40 9 .1 23 .2 0 .39 10 .8 25 .6 0 .42 9 .7 23 .8 0 .41
NOTE : ADH = antidiuretic hormone ; V - urine flow rate ; Ul n - concentration of inulin ; Cl o - clearance of inulin; UPAH = concentration of para-aminohippurate ; CPAH - clearance of para-aminohippurate ; UN a = concentration of sodium ; CN s = clearance of sodium .
The branches of the renal artery, both extrarenal and intrarenal, were the site of marked fibrous intimal plaque formation which produced significant narrowing of the arterial lumens . One small intrarenal artery contained an organized thrombus ; the corresponding cortical area was infarcted . Representative glomeruli from the left kidney
are shown in Figure 4 . The glorneruli were concentrated because of the tubular atrophy . Excluding the two areas of scar and infarction, all the glomeruli were intact although some focal hypercellularity could be found on careful search . No crescent formations or capsular adhesions were observed . The tubular epithelium did not show any abnormalities except for the de-
TABLE II RESULTS OF POSTOPERATIVE RENAL FUNCTION STUDIES *
GFR (Cla) (mi ./min .)
RPF (CpAR) (ml./min .)
Filtration Fraction (GFR/RPF)
7 .7
71
264
0 .27
22
1 .30
2 .20
144-162/96-110
10 .7
58
264
0 .22
22
1 .80
3 .11
164-178/110-120
8 .0
42
224
0 .19
40
2 .38
5 .66
140-150/90-94t
V (ml ./min.)
Date
3/22/63 (7 days after nephrectomv) 7/8/63 (15 wk . after nephrectomy) 3/11/65 (2 yr. after nephrectomy)
UN . (mEq ./L .)
CN s (ml ./min .)
% Filtered Na Excreted
Av . Blood Pressure (mm. Hg)
NOTE : V = urine flow rate ; GFR - glomerular filtration rate ; CIn = clearance of inulin ; RPF - renal plasma flow ; CPAg = clearance of para-aminohippurate ; UN, - concentration of sodium ; CNs - clearance of sodium . * Each study represents the average of three consecutive 45 minute collection periods for which an indwelling Foley catheter was used . A water diuresis was maintained by oral hydration ; an infusion of inulin and PAH was given in saline solution at a rate of 1 .1 ml . per minute. . .) t Antihypertensive therapy was started 30 days before this study . The therapy consisted of a saluretic, and guanethidine (5 mg . every 12 hr VOL .
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Unilateral Glomerulonephritis-Palmer et al. strikingly hypercellular . (Fig. 5 .) This hypercellularity was due to either epithelial or endothelial proliferation (or both) . However, few, if any, inflammatory cells were recognized. There were no capsular adhesions or crescent formations . Pigmented (degenerated red cell) casts were seen in the tubules . No evidence of pyelonephritis was found in the biopsy specimen. In both the biopsy specimen and the left kidney the arterioles showed considerable hyalinization which was thought to be secondary to the patient's hypertension . The glomerular alterations in the right kidney were interpreted as a proliferative acute glomerulonephritis . STUDIES OF RENAL FUNCTION
and C, three representative glomeruli from the excised left kidney . These glomeruli were essentially normal with the possible exception of equivocal focal hypercellularity . FIG . 4 . A, B
crease in cell size . With the exception of old blood casts adjacent to the infarct, the remainder of the tubular lumens in the left kidney were normal . The biopsy specimen of the right kidney showed only the cortex . Here the tubules revealed little or no atrophy. The glomeruli were
The results of preoperative differential renal studies are presented in Table I . The urine flow rate (V) from the left kidney was one-tenth that from the right kidney in all three periods . The PAH concentration (Up AH) was greater in urine from the left than in that from the right kidney by 280 per cent. This 280 per cent increase in UpAH in the left kidney, accompanied by a 10 :1 difference in V, is characteristic of functionally significant, unilateral main renal artery disease [2]. Renal plasma flow was 78 ml. per minute per 1 .73 M2. to the left kidney and 258 ml. per minute per 1 .73 M 2. to the right . Glomerular filtration rate was 18 ml. per minute per 1 .73 M2. in the left kidney and 70 ml . per minute per 1 .73 M2. in the right kidney . The filtration fraction was elevated in both kidneys although less so in the left kidney, a finding characteristic of functional main renal artery stenosis [3] . It is interesting to note that in this patient the urinary concentrations of sodium (U Na) were within 6 per cent of each other . However, the percentage of filtered sodium excreted (Table I) was markedly reduced in the left kidney compared with the right kidney-an observation explained by the increased equimolar reabsorption of filtered water and sodium in the proximal tubules of the ischemic kidney . Finally, the marked disparity in renal blood flow between the two kidneys is shown in Table I . The importance of renal plasma flow to the contralateral kidney in the prognosis of curable renal hypertension has recently been emphasized [3] . It has been pointed out that a renal plasma flow of 250 ml . per minute per 1 .73 M2. or less to the contralateral kidney has correlated AMERICAN JOURNAL O F MEDICINE
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closely with small vessel disease and failure to influence the patient's blood pressure by surgical intervention . The renal plasma flow of 258 ml . per minute to the contralateral kidney in this patient appeared to be a borderline reduction . The decrease in size of the involved left kidney, however, should have been associated with a corresponding hypertrophy of the contralateral side ; the observation that the plasma flow to the right kidney in this patient was only 258 ml . per minute was a disturbing finding . Renal function was measured three times in the two years following nephrectomy . (Table it .) Each study represented the average of three consecutive 45 minute collection periods ; an indwelling Foley catheter and oral water diuresis were used . The renal plasma flow to the retraining kidney was essentially unchanged one week and fifteen weeks after left nephrectomy . There was a gradual decrease in inulin clearance (C I ,), however, which may have indicated progression of the proliferative glomerular lesion . (Table II .) The most recent study was performed one month after initiating therapy with Ismelin® * and a saluretic . This study showed a further decrease in GFR and for the first time a decrease in renal plasma flow . The decrease in renal plasma flow, if not related to antihypertensive medication, indicated either progression of glomerulitis or arteriosclerosis . Since the filtration fraction progressively decreased, glomerulitis seems a more appropriate explanation than vascular disease . The persistent microscopic hematuria and mild proteinuria are compatible with the diagnosis of glomerulonephritis . COMMENTS
Since glomerulonephritis is a disease which "always involves both kidneys" [1], the presence of a unilateral lesion in this patient was unexpected . One of us (S .L .E .) remembered a clinicopathologic conference at Johns Hopkins Hospital in 1951 when Dr . Paul Kimmelstiel made reference to an autopsy performed on a patient in whom a unilateral glomerulitis was present . An associated renal artery stenosis was found at autopsy . Correspondence confirmed the recollection and he kindly allowed us to review the microscopic slides . The lesion in Dr . Kimmelstiel's patient showed a marked differ* Guanethidine, Ciba Pharmaceutical Co ., Summit, New Jersey . VOL .
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FIG . 5 . A, B and C, three representative glomeruli from the biopsied section of the right kidney . These show diffuse hypercellularity secondary to proliferation of epithelial (or endothelial) cells of the glomeruli ; there are no inflammatory cells .
ence in the right and left kidneys, but the type of nephritis seemed less clear-cut (S .L .E .) than in our patient . Unilateral glomerulonephritis is not unknown as an experimental model . In 1946 Reubi produced complete, unilateral hydronephrosis by
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Unilateral Glomerulonephritis-Palmer et al .
ligating the left ureteropelvic junction in two rabbits [4] . Ten days later he injected duck antirabbit kidney serum into their veins after the method of Masugi and Sato [5] . The animals were sacrificed within a month . In the right kidney of each rabbit glomerulonephritis had developed but the hydronephrotic left kidney showed distinctly less involvement . Reubi's work drew its inspiration from a case report by Fahr in 1943 [6] . Fahr had performed an autopsy on a woman who died from glomerulonephritis . The left kidney was small, with a dilated renal pelvis and calyces ; there was, however, general preservation of renal structure . Microscopic examination of the right kidney showed subacute glomerulonephritis . Although the left kidney was atrophic from hydronephrosis, there was no evidence of glomerular lesions . More recently, Rother and Sarre in 1962 rapidly injected duck antirabbit kidney serum into the veins of a series of rabbits [7] . They concurrently occluded the left renal artery for 20 minutes . During subsequent months the surviving animals were sacrificed . Five rabbits had unilateral chronic glomerulonephritis involving only the right kidney . Three had the same histologic picture in the right kidney, but slight glomerular changes in the occluded left kidney . Two rabbits had healed glomerulonephritis in the right kidney with a normal left kidney . Five animals had bilateral glomerulonephritis . Although it is difficult to explain the protective effect of unilateral hydronephrosis in preventing experimentally induced nephritis, the effect of complete unilateral renal arterial occlusion seems more obvious because the kidney is more or less protected from the infusion of foreign antigen for the duration of interference with arterial flow . Germuth has further documented the experiments of Rother and Sarre by producing chronic ischemia with renal artery constriction prior to inducing serumsickness nephritis in rabbits [8] . In each rabbit the kidney with ischemia and atrophy showed little or no glomerulonephritis . He also noted that the degree of glomerulitis seemed to be inversely proportional to the degree of ischemia . Germuth's work comes close to being the experimental model of our human case . In our patient a unilateral glomerulonephritis was found in the contralateral kidney whereas in the ischemic kidney the glomeruli, in general, were normal . This case report, together with the
experimental work of Germuth, suggests that a unilateral reduction in renal blood flow may delay or interfere with the development of glomerulonephritis in the ischemic kidney while the disease progresses in the opposite glomeruli . SUMMARY
We have presented what we believe to be the first documented case report of unilateral glomerulonephritis in structurally normal kidneys . Our patient had an ischemic kidney due to arteriosclerotic occlusive disease of the left main renal artery . She was hypertensive for many years before the appearance of red cells in the urine, suggesting that the renal artery occlusion may have occurred before the development of glomerulonephritis . Although slight focal hypercellularity was present in the ischemic left kidney, the biopsy specimen of the right kidney showed striking proliferative glomerulitis . Results of differential function studies performed before removal of the ischemic kidney are presented with those of follow-up clearance studies on the remaining glomerulonephritic kidney over a two year period . Pertinent work in the field of experimentally produced glomerulonephritis is cited and discussed . The results of studies carried out on this patient, as well as the unpublished experimental data of Germuth, seem to indicate that renal ischemia can play a role in the pathogenesis of glomerulonephritis . REFERENCES 1 . FISHSERG, A. M. Hypertension and Nephritis. Philadelphia, 1954 . Lea & Febiger . 2 . STAMEY, T. A . Renovascular Hypertension . Baltimore, 1963 . Williams & Wilkins Co . 3 . STAMEY, T. A . Antihypertensive therapy . In : Ciba Foundation Symposium. Heidelberg, 1966. Springer-Verlag . 4 . REUBI, F . Hydronephrose et glomerulonephrite (etude experimental) . Schweiz . med. Wchnschr., 76 : 457, 1946. 5 . MASUGI, M . and SATO, Y . UberdieallergischeGewebsreaktion der Niere. Zugleich ein experimenteller Beitrag zur Pathogenese der diffusen Glomerulonephritis and der Periarteriitis Nodosa . Virchow's Arch . path. Anal ., 293 : 615, 1934. 6. FAHR, T . Die Funktionsbehinderung der Niere als hemmendes Moment bei der Entwicklung von Glomerulonephritis and maligner Nephrosklerose . Deutsche Arch . klin. med., 191 : 52, 1943 . 7 . ROTHER, K . and SARRE, H. Untersuchungen zur pathogenetischen Bedeutung der Autoantikorper : Einseitige experimentelle chronische Glomerulonephritis . Min. Wchnschr., 40 : 429, 1962 . 8 . GERMUTH, F . G ., JR. Personal communication .
AMERICAN JOURNAL O F MEDICINE
LOMERULONEPHRITIS has been accepted as a disease which always involves both kidneys [1] . However, we have recently studied a patient who seems to be an exception to this rule . This patient was hypertensive and had occlusive vascular disease in the left main renal artery . A left nephrectomy and a biopsy of the right kidney were performed . The biopsy specimen revealed a diffuse, proliferative glomerulonephritis which was not present in the left kidney .
G
CASE REPORT E .C . (No . 11-29-39), a fifty-seven year old Caucasian housewife, was first seen at the Stanford Medical Center on February 11, 1963, for evaluation of hypertension . She was known to be hypertensive since her only pregnancy fifteen years previously, but had received no therapy other than mild sedatives . In 1960 microscopic hematuria and proteinuria were noted for the first time . An intravenous pyelogram showed a left renal mass . Blood pressure readings ranged from 160/110 to 200/120 mm . Hg . Exploratory examination of the left kidney was performed at another hospital and a small renal cyst was found . The cyst was opened but a renal biopsy was not performed . In 1962 the patient was readmitted because of mild gastrointestinal complaints ; the blood pressure was 210/110 mm . Hg . Microscopic hematuria was again noted, with 2+ proteinuria . Cystoscopy and retrograde pyelograms failed to reveal the etiology of the microscopic hematuria. In October 1962 easy fatigability, cardiac palpitations and occasional dull precordial pain without radiation prompted the patient to seek medical advice . The blood pressure was 200/120 mm . Hg . Urinalysis revealed 4+ proteinuria with 40 to 50 red cells per high power field and occasional hyaline casts . Mild occipital headaches became more severe, and she was referred to the Stanford Medical Center. There was no history of streptococcal infection or
rheumatic fever. The patient had had typhoid fever at six years of age . Her mother had been hypertensive and died of a stroke at the age of seventy-three . On physical examination the patient was afebrile and in no acute distress . Moderate obesity was present. Blood pressure was 170/110 mm . Hg . Her peripheral vision was decreased and examination of the optic fundi revealed retinitis pigmentosa ; grade 1 hypertensive retinopathy was also present. The neck veins were flat. The lungs were clear to percussion and auscultation, and the heart was not enlarged on clinical examination . No cardiac murmurs were present . The right kidney was palpable . There were no abdominal bruits. The pedal pulses were decreased although palpable. The remainder of the examination was within normal limits .
LABORATORY STUDIES The hematocrit was 40 per cent, hemoglobin 14 .5 gm . per cent white blood cell count 10,700 per cu . mm, with a normal differential, and erythrocyte sedimentation rate 31 mm . per hour . Specific gravity of a random urine sample was 1 .013 ; there was 1+ proteinuria . Urinalysis for glucose was negative . Microscopic examination of the urinary sediment revealed 8 to 10 red cells and 1 to 3 white cells per high power field ; 1 granular cast was seen on the slide . No red cell casts were present on multiple urine examinations . Several urine cultures were sterile . The serum creatinine was 1 .2 mg . per cent, and the serum electrolytes were normal . A 24 hour urine protein determination showed 0 .54 gm . The antistreptolysin 0 titer was 166 Todd units ; this elevated titer was thought to be compatible with a previous streptococcal infection . Serum total protein was 7 .2 gm . per 100 ml . Serum protein electrophoresis showed 54 per cent albumin and 46 per cent globulin with 4 per cent alpha,, 13 per cent alpha2, 10 per cent
* From the Division of Urology and Surgical Pathology, Stanford University School of Medicine, Palo Alto, California . Manuscript received September 17, 1965 . 816
AMERICAN JOURNAL OF MEDICINE
Unilateral Glomerulonephritis---Pahner
et al .
817
FIG. 1 . A, an intravenous pyelogram ob a ned fi e months a er exploratory examination uc the e kidney for hematuria . There was a 1 .7 cm . difference in renal size . B, a retrograde pyelogram obtained three }ears after examination of the left kidney . The cortical margins are easily discernible ; there was uniform cortical atrophy and a 3 .2 cm. difference in renal size .
FIG . 2 . Rapid-sequence films (intravenous pyelogram) . A, I minute film . '1 'he nephrogram of the left kidney appears more dense . B, 2 minute film . The contrast medium had reached the calyces and pelves of both kidneys at the same time . C, 3 minute film . The calyces and pelvis of the left kidney appear smaller than the right, suggesting a decreased urine volume . D, 5 minute film . There is no evidence of hyperconcentration of the contrast medium in the left kidney .
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3B
FIG . 3 . A, transfemoral abdominal aortogram . There is marked stenosis of the left main renal artery near its ostium . The right renal artery and its branches are not obstructed . Severe arteriosclerotic involvement of the aorta is present and aneurysmal dilation is seen above the celiac axis . B, the severity of the stenosis in the left renal artery is emphasized by the left posterior oblique position .
beta and 19 per cent gamma globulins . A roentgenogram of the chest indicated normal lung fields and left ventricular enlargement ; the electrocardiogram demonstrated left axis deviation . Figure 1A is from an intravenous pyelogram obtained five months after the left renal exploration in 1960 . Figure 1B is from a retrograde pyelogram performed in 1963 ; a 1 .5 cm. decrease in left renal size is apparent . Although it is sometimes fallacious to compare a retrograde with an intravenous pyelogram, the renal shadows were well seen in each study and both series were made at the same radiologic unit . In March 1963 an intravenous pyelogram was obtained at Stanford . (Fig . 2 .) There was a prompt nephrogram bilaterally at 1 minute (Fig . 2A), seemingly more dense in the left kidney. By 2 minutes, contrast material had reached the collecting system of each kidney. (Fig . 2B .) Although there was no delay in excretion of contrast material by the left kidney and no clear-cut evidence of hyperconcentration on that side, there had been a striking decrease in left renal size since 1960 . Transfemoral arteriography demonstrated a localized stenotic obstruction of the left renal artery at its origin . (Fig . 3 .) There was fusiform aneurysmal dilation of the abdominal aorta just above the celiac axis, and extensive arteriosclerotic changes were present below the renal arteries . Differential renal function studies were performed (Table I) using an infusion of urea, saline solution and antidiuretic hormone (ADH) . There was a 10 :1 difference in urine flow rates
with a 280 per cent increase in the concentration of para-aminohippurate (PAH) in the left kidney . On March 15, 1964, the abdomen was explored . The blood pressure in the abdominal aorta was 138/96 mm . Hg ; the blood pressure in the renal artery distal to the obstruction was 108/86 mm . Hg . Because of the patient's age and the severe arteriosclerosis of the abdominal aorta, a left nephrectomy and a wedge biopsy of the right kidney were performed . The postoperative course was uneventful . The blood pressure did not change significantly . In the hospital prior to left nephrectomy it was 157/101 mm . Hg . (an average of seventy-seven readings) ; following surgery it was 153/99 mm . Hg (an average of seventy-four readings) . The remaining kidney was studied three times during the following two years ; an indwelling Foley catheter and oral water hydration were used for each study . (Table II .) The urine continued to show 20 to 40 red blood cells per high power field and 5 to 20 mg . of protein per 100 ml . The most recent urinalysis, performed on March 11, 1965, revealed 5 mg . of protein per 100 ml ., 10 to 40 red cells per high power field and 1 to 3 granular casts per low power field . The blood pressure was unchanged until the most recent visit when, one month after initiation of antihypertensive medication, it was 142/90 mm . Hg . PATHOLOGIC STUDIES
The left kidney weighed 100 gm . and the cortex measured less than 4 mm . in thickness . A dilated calyx beneath a small cortical scar at one pole of the kidney contained an impacted stone . AMERICAN JOURNAL O F MEDICINE
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81 9
TABLE I RESULTS OF PREOPERATIVE DIFFERENTIAL RENAL FUNCTION STUDY (MARCH 13, 1964)
`rime (min .)
--50 -41 -40 -31 -30 -28
Data
Blood pressure 192/122 mm . Hg Infusion of 8 % urea in normal saline solution started at 9 .6 ml./ min . t o deliver 1 .50 mg./ml . inulin, 1 .01 mg./ml . PAH and 5 mtJ ./kg ./ hr. ADH 21 .9 ml . 10% inulin and 2 .4 ml . 20% PAH injected intravenously 1 ml . 0 .25% heavy Nupercaine® injected into 4th lumbar interspace for saddle anesthesia 292 mU . ADH injected intravenously Blood pressure 190/130 mm . Hg No . 8 French polyethylene catheter passed to left mid-ureter No. 7 French polyethylene catheter passed to right mid-ureter Blood pressure 206/124 mm . Hg
% Filtered Na Excreted CNs ((CNa/Cln) X (ml./min .) 100)
Kidney
V (ml ./ min .)
Uia (mg./100 ml .)
Cl . (ml./min ./ 173 M2 .)
UPAB (mg./100 ml .)
14-24
Left Right Left/Right
2 .32 21 .68 0 .11
157 .1 68 .2 2 .30
18 71 0 .25
93 .3 31 .7 2 .94
83 264 0 .31
0 .22 0 .27 0 .81
95 .4 100 .4 0 .95
1 .64 16 .10 0 .10
24-34
Left Right Left/Right
2 .35 22 .20 0 .11
18 70 0 .26
83 .6 30 .7 2 .72
94 .1 99 .1 0 .95
Left Right Left/Right
2 .62 24 .00 0 .11
17 69 0 .25
73 .1 26 .9 2 .72
76 262 0 .29 74 248 0 .30
0 .24 0 .27 0 .89
34-44
155 .4 65 .6 2 .37 134 .9 60 .2 2 .24
0 .23 0 .28 0 .82
95 .1 99 .4 0 .96
1 .64 16 .27 0 .10 1 .84 17 .64 0 .10
14-44 (Av .)
Left Right Left/Right
2 .43 22 .63 0 .11
149 .1 64 .7 2 .30
18 70 0 .26
83 .3 29 .8 2 .80
78 258 0 .30
0 .23 0 .27 0 .85
94 .9 99 .6 0 .95
1 .71 16 .67 0 .10
Time (min .)
CPAE Filtration (ml./min / Fraction 173 MI .) (Cl n /CPAH)
UN. (mEq ./L .)
9 .1 22 .7 0 .40 9 .1 23 .2 0 .39 10 .8 25 .6 0 .42 9 .7 23 .8 0 .41
NOTE : ADH = antidiuretic hormone ; V - urine flow rate ; Ul n - concentration of inulin ; Cl o - clearance of inulin; UPAH = concentration of para-aminohippurate ; CPAH - clearance of para-aminohippurate ; UN a = concentration of sodium ; CN s = clearance of sodium .
The branches of the renal artery, both extrarenal and intrarenal, were the site of marked fibrous intimal plaque formation which produced significant narrowing of the arterial lumens . One small intrarenal artery contained an organized thrombus ; the corresponding cortical area was infarcted . Representative glomeruli from the left kidney
are shown in Figure 4 . The glorneruli were concentrated because of the tubular atrophy . Excluding the two areas of scar and infarction, all the glomeruli were intact although some focal hypercellularity could be found on careful search . No crescent formations or capsular adhesions were observed . The tubular epithelium did not show any abnormalities except for the de-
TABLE II RESULTS OF POSTOPERATIVE RENAL FUNCTION STUDIES *
GFR (Cla) (mi ./min .)
RPF (CpAR) (ml./min .)
Filtration Fraction (GFR/RPF)
7 .7
71
264
0 .27
22
1 .30
2 .20
144-162/96-110
10 .7
58
264
0 .22
22
1 .80
3 .11
164-178/110-120
8 .0
42
224
0 .19
40
2 .38
5 .66
140-150/90-94t
V (ml ./min.)
Date
3/22/63 (7 days after nephrectomv) 7/8/63 (15 wk . after nephrectomy) 3/11/65 (2 yr. after nephrectomy)
UN . (mEq ./L .)
CN s (ml ./min .)
% Filtered Na Excreted
Av . Blood Pressure (mm. Hg)
NOTE : V = urine flow rate ; GFR - glomerular filtration rate ; CIn = clearance of inulin ; RPF - renal plasma flow ; CPAg = clearance of para-aminohippurate ; UN, - concentration of sodium ; CNs - clearance of sodium . * Each study represents the average of three consecutive 45 minute collection periods for which an indwelling Foley catheter was used . A water diuresis was maintained by oral hydration ; an infusion of inulin and PAH was given in saline solution at a rate of 1 .1 ml . per minute. . .) t Antihypertensive therapy was started 30 days before this study . The therapy consisted of a saluretic, and guanethidine (5 mg . every 12 hr VOL .
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Unilateral Glomerulonephritis-Palmer et al. strikingly hypercellular . (Fig. 5 .) This hypercellularity was due to either epithelial or endothelial proliferation (or both) . However, few, if any, inflammatory cells were recognized. There were no capsular adhesions or crescent formations . Pigmented (degenerated red cell) casts were seen in the tubules . No evidence of pyelonephritis was found in the biopsy specimen. In both the biopsy specimen and the left kidney the arterioles showed considerable hyalinization which was thought to be secondary to the patient's hypertension . The glomerular alterations in the right kidney were interpreted as a proliferative acute glomerulonephritis . STUDIES OF RENAL FUNCTION
and C, three representative glomeruli from the excised left kidney . These glomeruli were essentially normal with the possible exception of equivocal focal hypercellularity . FIG . 4 . A, B
crease in cell size . With the exception of old blood casts adjacent to the infarct, the remainder of the tubular lumens in the left kidney were normal . The biopsy specimen of the right kidney showed only the cortex . Here the tubules revealed little or no atrophy. The glomeruli were
The results of preoperative differential renal studies are presented in Table I . The urine flow rate (V) from the left kidney was one-tenth that from the right kidney in all three periods . The PAH concentration (Up AH) was greater in urine from the left than in that from the right kidney by 280 per cent. This 280 per cent increase in UpAH in the left kidney, accompanied by a 10 :1 difference in V, is characteristic of functionally significant, unilateral main renal artery disease [2]. Renal plasma flow was 78 ml. per minute per 1 .73 M2. to the left kidney and 258 ml. per minute per 1 .73 M 2. to the right . Glomerular filtration rate was 18 ml. per minute per 1 .73 M2. in the left kidney and 70 ml . per minute per 1 .73 M2. in the right kidney . The filtration fraction was elevated in both kidneys although less so in the left kidney, a finding characteristic of functional main renal artery stenosis [3] . It is interesting to note that in this patient the urinary concentrations of sodium (U Na) were within 6 per cent of each other . However, the percentage of filtered sodium excreted (Table I) was markedly reduced in the left kidney compared with the right kidney-an observation explained by the increased equimolar reabsorption of filtered water and sodium in the proximal tubules of the ischemic kidney . Finally, the marked disparity in renal blood flow between the two kidneys is shown in Table I . The importance of renal plasma flow to the contralateral kidney in the prognosis of curable renal hypertension has recently been emphasized [3] . It has been pointed out that a renal plasma flow of 250 ml . per minute per 1 .73 M2. or less to the contralateral kidney has correlated AMERICAN JOURNAL O F MEDICINE
Unilateral Glomerulonephritis
Palmer et al .
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closely with small vessel disease and failure to influence the patient's blood pressure by surgical intervention . The renal plasma flow of 258 ml . per minute to the contralateral kidney in this patient appeared to be a borderline reduction . The decrease in size of the involved left kidney, however, should have been associated with a corresponding hypertrophy of the contralateral side ; the observation that the plasma flow to the right kidney in this patient was only 258 ml . per minute was a disturbing finding . Renal function was measured three times in the two years following nephrectomy . (Table it .) Each study represented the average of three consecutive 45 minute collection periods ; an indwelling Foley catheter and oral water diuresis were used . The renal plasma flow to the retraining kidney was essentially unchanged one week and fifteen weeks after left nephrectomy . There was a gradual decrease in inulin clearance (C I ,), however, which may have indicated progression of the proliferative glomerular lesion . (Table II .) The most recent study was performed one month after initiating therapy with Ismelin® * and a saluretic . This study showed a further decrease in GFR and for the first time a decrease in renal plasma flow . The decrease in renal plasma flow, if not related to antihypertensive medication, indicated either progression of glomerulitis or arteriosclerosis . Since the filtration fraction progressively decreased, glomerulitis seems a more appropriate explanation than vascular disease . The persistent microscopic hematuria and mild proteinuria are compatible with the diagnosis of glomerulonephritis . COMMENTS
Since glomerulonephritis is a disease which "always involves both kidneys" [1], the presence of a unilateral lesion in this patient was unexpected . One of us (S .L .E .) remembered a clinicopathologic conference at Johns Hopkins Hospital in 1951 when Dr . Paul Kimmelstiel made reference to an autopsy performed on a patient in whom a unilateral glomerulitis was present . An associated renal artery stenosis was found at autopsy . Correspondence confirmed the recollection and he kindly allowed us to review the microscopic slides . The lesion in Dr . Kimmelstiel's patient showed a marked differ* Guanethidine, Ciba Pharmaceutical Co ., Summit, New Jersey . VOL .
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FIG . 5 . A, B and C, three representative glomeruli from the biopsied section of the right kidney . These show diffuse hypercellularity secondary to proliferation of epithelial (or endothelial) cells of the glomeruli ; there are no inflammatory cells .
ence in the right and left kidneys, but the type of nephritis seemed less clear-cut (S .L .E .) than in our patient . Unilateral glomerulonephritis is not unknown as an experimental model . In 1946 Reubi produced complete, unilateral hydronephrosis by
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Unilateral Glomerulonephritis-Palmer et al .
ligating the left ureteropelvic junction in two rabbits [4] . Ten days later he injected duck antirabbit kidney serum into their veins after the method of Masugi and Sato [5] . The animals were sacrificed within a month . In the right kidney of each rabbit glomerulonephritis had developed but the hydronephrotic left kidney showed distinctly less involvement . Reubi's work drew its inspiration from a case report by Fahr in 1943 [6] . Fahr had performed an autopsy on a woman who died from glomerulonephritis . The left kidney was small, with a dilated renal pelvis and calyces ; there was, however, general preservation of renal structure . Microscopic examination of the right kidney showed subacute glomerulonephritis . Although the left kidney was atrophic from hydronephrosis, there was no evidence of glomerular lesions . More recently, Rother and Sarre in 1962 rapidly injected duck antirabbit kidney serum into the veins of a series of rabbits [7] . They concurrently occluded the left renal artery for 20 minutes . During subsequent months the surviving animals were sacrificed . Five rabbits had unilateral chronic glomerulonephritis involving only the right kidney . Three had the same histologic picture in the right kidney, but slight glomerular changes in the occluded left kidney . Two rabbits had healed glomerulonephritis in the right kidney with a normal left kidney . Five animals had bilateral glomerulonephritis . Although it is difficult to explain the protective effect of unilateral hydronephrosis in preventing experimentally induced nephritis, the effect of complete unilateral renal arterial occlusion seems more obvious because the kidney is more or less protected from the infusion of foreign antigen for the duration of interference with arterial flow . Germuth has further documented the experiments of Rother and Sarre by producing chronic ischemia with renal artery constriction prior to inducing serumsickness nephritis in rabbits [8] . In each rabbit the kidney with ischemia and atrophy showed little or no glomerulonephritis . He also noted that the degree of glomerulitis seemed to be inversely proportional to the degree of ischemia . Germuth's work comes close to being the experimental model of our human case . In our patient a unilateral glomerulonephritis was found in the contralateral kidney whereas in the ischemic kidney the glomeruli, in general, were normal . This case report, together with the
experimental work of Germuth, suggests that a unilateral reduction in renal blood flow may delay or interfere with the development of glomerulonephritis in the ischemic kidney while the disease progresses in the opposite glomeruli . SUMMARY
We have presented what we believe to be the first documented case report of unilateral glomerulonephritis in structurally normal kidneys . Our patient had an ischemic kidney due to arteriosclerotic occlusive disease of the left main renal artery . She was hypertensive for many years before the appearance of red cells in the urine, suggesting that the renal artery occlusion may have occurred before the development of glomerulonephritis . Although slight focal hypercellularity was present in the ischemic left kidney, the biopsy specimen of the right kidney showed striking proliferative glomerulitis . Results of differential function studies performed before removal of the ischemic kidney are presented with those of follow-up clearance studies on the remaining glomerulonephritic kidney over a two year period . Pertinent work in the field of experimentally produced glomerulonephritis is cited and discussed . The results of studies carried out on this patient, as well as the unpublished experimental data of Germuth, seem to indicate that renal ischemia can play a role in the pathogenesis of glomerulonephritis . REFERENCES 1 . FISHSERG, A. M. Hypertension and Nephritis. Philadelphia, 1954 . Lea & Febiger . 2 . STAMEY, T. A . Renovascular Hypertension . Baltimore, 1963 . Williams & Wilkins Co . 3 . STAMEY, T. A . Antihypertensive therapy . In : Ciba Foundation Symposium. Heidelberg, 1966. Springer-Verlag . 4 . REUBI, F . Hydronephrose et glomerulonephrite (etude experimental) . Schweiz . med. Wchnschr., 76 : 457, 1946. 5 . MASUGI, M . and SATO, Y . UberdieallergischeGewebsreaktion der Niere. Zugleich ein experimenteller Beitrag zur Pathogenese der diffusen Glomerulonephritis and der Periarteriitis Nodosa . Virchow's Arch . path. Anal ., 293 : 615, 1934. 6. FAHR, T . Die Funktionsbehinderung der Niere als hemmendes Moment bei der Entwicklung von Glomerulonephritis and maligner Nephrosklerose . Deutsche Arch . klin. med., 191 : 52, 1943 . 7 . ROTHER, K . and SARRE, H. Untersuchungen zur pathogenetischen Bedeutung der Autoantikorper : Einseitige experimentelle chronische Glomerulonephritis . Min. Wchnschr., 40 : 429, 1962 . 8 . GERMUTH, F . G ., JR. Personal communication .
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