Clinical Science and Molecular Medicine (1978), 54, 649-659
Renal function in chronic obstructive jaundice:
a micropuncture study in rats
MARJORIE E. M. ALLISON, N. G. MOSS, MARY M. FRÄSER, J. W. DOBBIE,
C. J. RYAN, A. C. KENNEDY AND L. H. BLUMGART
University Departments of Medicine and Surgery, Glasgow Royal Infirmary, Glasgow, Scotland, U.K.
(Received 27 July 1977; accepted 30 January 1978)
Summary
1. We have studied kidney structure and func­
tion in female Sprague-Dawley rats with chronic
obstructive jaundice after bile-duct ligation and
section and in age-matched sham-operated control
animals.
2. High bile-duct ligation and section resulted in
immediate hyperbilirubinaemia and progressive
hepatomegaly with histological evidence of bileduct proliferation and periportal inflammation and
flbrosis.
3. Only 20% of the jaundiced animals developed
ascites, but 42% became hypotensive and died
during preparation for micropuncture.
4. In the surviving rats there was no significant
change in blood pressure, whole-kidney glomerular
filtration rate, single-nephron glomerular filtration
rate or calculated glomerular capillary hydrostatic
pressure from control animals. However, renal
plasma flow was increased so that whole-kidney
filtration fraction was low. These changes were
largely reversed by choledochoduodenostomy.
5. Proximal tubular reabsorption in the jaun­
diced group was not different from control rats,
although the inulin (urine/plasma) ratio was sig­
nificantly reduced, indicating diminished reab­
sorption distal to the proximal convoluted tubule.
Proximal intratubular hydrostatic pressure was sig­
nificantly increased in some nephrons.
6. Electron microscopy of the glomeruli from
the jaundiced animals revealed evidence of marked
increase in activity of both epithelial and endothelial cells.
7. Rats who survive chronic obstructive jaun­
dice for 3-4 weeks have changes in renal function
and also structural changes suggestive of
diminished glomerular permeability.
Key words: kidney, micropuncture, obstructive
jaundice.
Correspondence: Dr Marjorie E. M. Allison, Tenovus Kidney
Diseases Research Unit, Royal Infirmary, Glasgow G4 OSF,
Scotland, U.K.
649
Abbreviations: [PJ, arterial plasma protein con­
centration; Pg, glomerular capillary hydrostatic
pressure; π,, oncotic pressure; PAH, paminohippurate.
Introduction
Obstructive jaundice has long been known to
increase the risk of acute renal failure after surgery
(Clairmont & von Haberer, 1911; Ravdin, 1929;
Heyd, 1931; Helwig & Schutz, 1932; Wilbur,
1934; Williams, Elliot & Zollinger, 1960; FunckBrentano, Mery, Vantelon & Watchi, 1963; Dawson, 1965a; S0rensen, Anderson, 0rnsholt &
Skjoldborg, 1971). Changes in kidney structure
have been described in obstructive jaundice. Early
light-microscopy studies reported degenerative
changes in the proximal convoluted tubules
together with the presence of pigment casts
(Wilbur, 1934; Ayer, 1938). More recently,
electron microscopy of the glomeruli has shown
fusion of epithelial foot processes, considerable
thickening of the basement membranes and black
granules in the basement membrane and sub-endothelial space (Sakaguchi, Dachs, Grisham &
650
M. E.M.Allison
Churg, 1965; Arhelger, Davis, Evers, Henson &
Hardy, 1970).
In patients with obstructive jaundice and in
experimental animals, however, studies of kidney
function have given conflicting and inconclusive
results (Elsom, 1937; Popper & Schaffner, 1957;
Cattell & Birnstingl, 1964; Dawson, 1965b). Some
investigators have reported little or no change in
renal function (Fajers, 1957; Cattell & Birnstingl,
1964; Dawson, 1968) whereas others have found
sodium retention, with ascites and a fall in
glomerular filtration rate and renal plasma flow
(Gliedman, Carroll, Popowitz & Mullane, 1970;
Maroske, Bichler, Naber, Hupe, Muller, Obrowski,
Schreiber & Haas, 1971; Better & Massry, 1972).
We have used clearance, micropuncture, lightand electron-microscopy techniques to study kid­
ney structure and single-nephron function in rats
who have had obstructive jaundice for 3-4 weeks.
Subtle, but consistent, changes in glomerular
structure and function and in tubular function were
found. There was no evidence in the rats studied
that obstructive jaundice of this duration altered
proximal fractional reabsorption.
Methods
Obstructive jaundice
Fifty female Sprague—Dawley rats, weighing
150-200 g (Bantin and Kingman Ltd, Grimston,
Aldbrough, Hull, North Humberside, U.K.) and
fed with regular rat chow (Oxoid 4IB) ad libitum
were anaesthetized with ether. The abdomen was
opened and the common bile duct was identified,
doubly ligated and divided just distal to its for­
mation (Lee, 1972; Wright & Braithwaite, 1962).
Neither vitamin K 1 (Lee, 1972) nor antibiotics
(Yarger, 1976) were given to the animals.
Clearance and micropuncture studies were car­
ried out on the 29 long-term survivors 24 ± 9 days
later.
In a separate group of eight rats choledochoduodenostomy was carried out as previously
described (Ryan, Than Than & Blumgart, 1977),
13-28 days after bile-duct ligation.
Control rats
Female Sprague-Dawley rats of the same
source, age and feeding as the jaundiced rats, had a
laparotomy and sham bile-duct ligation carried out
et al.
under ether anaesthesia. Clearance and micro­
puncture studies were carried out 34 ± 1 7 days
later.
Clearance studies
The rats were deprived of food but not water
overnight before study and were anaesthetized with
intraperitoneal sodium pentobarbital, 50 mg/kg
body weight. The rats were placed on a thermoregulated electric blanket to maintain their central
body temperature at 36° + 0-5°C and they were
prepared for micropuncture (Gottschalk & Mylle,
1956). An arterial blood sample (30 μ\) was
immediately obtained for measurement of baseline
packed cell volume, plasma urea and protein
concentration values.
Both ureters were cannulated with PE10 poly­
ethylene tubing. Blood pressure was recorded
continuously from either the carotid or femoral
artery with a Statham P23Db transducer (Statham
Instruments, Oxnard, CA, U.S.A.).
Sodium chloride solution (154 mmol/1; saline)
was given intravenously at the rate of 0-4 ml/100 g
body weight per hour, together with [3H]methoxyinulin and p-[14C]aminohippurate (New England
Nuclear Corp.). In those rats in which only intratubular pressure measurements were to be made a
priming dose of 80 ,uCi of [3H]inulin and 4 /iCi of
/>-[14C]aminohippurate was followed by a con­
tinuous infusion of [3H]inulin at a rate of 40 /iCi
r r 1 100 g"1 body weight and p-[' 4 C)aminohippurate at a rate of 4 ,uCi/h. When proximal
tubular fluid collections were to be made, this
infusion was increased to 60 /zCi of [3H]methoxyinulin h~' 100 g"1 body weight.
After 1 h for equilibration three consecutive
timed urine collections, each lasting approximately
40 min, were made from each kidney. Blood (30 μΐ)
was taken from the carotid or femoral artery and
renal vein at approximately the midpoint of each
collection for determination of packed cell volume
and protein, inulin and p-aminohippurate con­
centrations. Clearances were determined as pre­
viously described (Allison, Lipham, Lassiter &
Gottschalk, 1973). Glomerular filtration rate was
calculated separately for the left and right kidneys.
Renal plasma flow (RPF) and renal blood flow
(RBF) were calculated for the left kidney only,
from clearance (C) and extraction (£) of p-aminohippurate: RPF = C PAH /£ PAH ; RBF = RPF/(l-0 packed cell volume). Glomerular filtration rate,
C PAH , RPF and RBF have been expressed as ml
min^1 g _1 of kidney.
Renal/unction in obstructive jaundice
Single-nephron glomerular filtration rate and
percentage reabsorption
These measurements were made in ten rats with
obstructive jaundice and 11 sham-operated rats.
The kidney was bathed with water-equilibrated
mineral oil and timed samples of tubularfluidwere
obtained from various parts of the proximal
convoluted tubule through sharpened siliconized
glass pipettes, external tip diameter 8-12 //m, filled
with water-equilibrated mineral oil. The number of
loops visible on the surface of the kidney beyond
the point at which the pipette had been inserted
were counted by following the passage of a tiny
droplet of mineral oil as it travelled down the
nephron. In most instances one to nine loops were
visible 'downstream'. This method of loop iden­
tification in the proximal tubule was checked by an
'upstream' intratubular injection of isotonic saline
coloured with FD and C green dye (Keystone
Aniline and Chemical Co., Chicago, U.S.A.) via a
pipette of tip diameter about 5 μτα. When the
position of the pipette had been defined, a long
mineral oil block (four to five tubular diameters in
length) was injected into the nephron. Tubular fluid
was collected by suction, which was adjusted to
keep the oil block in place and the tubular diameter
constant if this was possible. The sample was
placed under water-equilibrated mineral oil on a
siliconized watch glass, its volume was measured
with a micropipette and it was then transferred into
liquid scintillation counting fluid (NE 260, Nuclear
Enterprises, Sighthill, Edinburgh, Scotland, U.K.).
The single-nephron glomerular filtration rate was
calculated as: fluid/plasma inulin ratio x tubular
flow rate (nl/min), and the percentage reabsorption
to the late proximal convolution was calculated as
100[1 — (1/fluid/plasma inulin ratio)].
Absolute reabsorption (nl/min) = fractional
reabsorption x single-nephron glomerular filtration
rate.
Hydrostatic pressure
This measurement was made in six rats with
obstructive jaundice, in two of which no clearances
were measured, and in 11 sham-operated control
rats. The kidney was bathed with saline heated to
36° ± 1°C to allow use of an electronic servonulling device (Allison, Lipham & Gottschalk,
1972). Sharpened siliconized glass pipettes, tip
diameter 3-5 μνα, filled with sodium chloride
solution (0·5 mol/1) were used and hydrostatic
pressure in proximal tubules was measured during
free flow and during stop flow after insertion of a
651
castor oil block downstream. Glomerular capillary
hydrostatic pressure (Pg) was calculated as the sum
of the stop-flow pressure and the afferent oncotic
pressure (Allison et al., 1972).
Arterial plasma protein concentrations ([Pa])
were measured before, during and at the end of
each experiment by an adaptation of the Lowry
technique (Brenner, Falchuk, Keimowitz & Ber­
liner, 1969) with human serum albumin used as
standard. Oncotic pressure (π„) was calculated as:
π„ = 2· 1 [Pa] + 0- 16[PaP + 0-009[Pj3
[Landis & Pappenheimer (1963) equation, which
has been validated for rat plasma (Allison, Wilson
& Gottschalk, 1974; Arendshorst, Finn &
Gottschalk, 1975)].
At the end of each experiment blood was
removed for measurement of serum bilirubin
concentration (Brayshaw, 1971). Urine and plasma
electrolytes were measured on an IL direct-reading
flame photometer (Instrumentation Laboratories,
Watertown, Mass., U.S.A.). Plasma urea concen­
tration was determined by a micro-adaptation of
the method of Fawcett & Scott (1960). The results
are given as mean ±SD. The significance of the
differences between mean values for jaundice and
control rats was assessed by Student's i-test.
Microinjection studies
Microinjection experiments were carried out on
eight rats with obstructive jaundice and in 14 nonoperated control rats as previously described
(Gottschalk, Morel & Mylle, 1965). The animals
were infused with sodium chloride solution (20 g/1)
at a rate of 5-8 ml/h and PE 50 polyethylene
catheters were placed in both ureters. A known
volume (0-5-3 nl) of [3H]methoxyinulin (New
England Nuclear Corp.) coloured with FD and C
green or nigrosin was injected slowly over 30-60 s
into superficial proximal tubules, and the percen­
tage of the measured injected volume recovered
from each kidney over the following 20 min was
calculated.
Microscopy studies
At the end of each experiment both kidneys and
the liver from each animal were weighed. One-half
of the left kidney was fixed in buffered formalin
for light-microscopy. Small pieces from the cortex
of the left kidney werefixedin 2% or 4% buffered
glutaraldehyde for electron microscopy. Sections of
the liver from the jaundiced animals werefixedin
buffered formalin for light-microscopy.
652
M. E. M. Allison et al.
High bile-duct ligation
Results
General characteristics
Ligation and section of the common bile duct
was carried out in 50 female Sprague-Dawley rats
(Fig. 1). All became jaundiced and survived for 26
± 10 days, when they were prepared for micropuncture. Ten rats developed ascites, (volume =
0-8-23-7 ml, mean 7-7 + 8-3 ml). Twenty-one
(42%) of the rats died because of hypotension, two
before the anaesthesia, the rest during preparative
surgery, including nine of the ten rats with ascites.
Clearance, micropuncture or microinjection
studies were carried out on the remaining 29 (58%
of the jaundiced rats). Table 1 shows features of
these survivors, the rats which died and the 15
sham-operated rats. The weight gain was sig­
nificantly less in the jaundiced rats and their liver
weight increased progressively with the duration of
juandice, so that after 5-6 weeks it was 21—26 g.
The packed cell volume was lower and the plasma
urea concentrations were higher in the two groups
of jaundiced rats, compared with the shamoperated rats, but there was no difference in kidney
weight or plasma protein concentration between
the three groups.
Urine osmolality fell dramatically within 24 h of
bile-duct obstruction (jaundice: before 1793 ± 431
mosmol/kg, after 542 ± 187 mosmol/kg; control:
before 1823 ± 251 mosmol/kg, after 1388 ± 529
mosmol/kg) and remained low. Water intake was
unchanged but sodium and protein intake fell
significantly.
After killing all animals were found to have had
complete ligation and section of their common bile
duct and there was no evidence of recanalization.
Clearance studies
Nineteen of the 29 rats which survived had
clearance observations carried out together with
tubular fluid collection or measurement of intratubular hydrostatic pressure. We have chosen to
use the clearance data from only those 12 rats
who received both p-[ u C]aminohippurate and
[3H]methoxyinulin. Clearance data are given for
the left kidney, there being no statistically signifi­
cant difference between the right and left kidney
glomerular filtration rates.
Table 2 gives the clearance data for the left
kidney in the 12 rats with obstructive jaundice and
in 15 sham-operated control rats. The jaundiced
rats had a significantly decreased inulin
(urine/plasma) ratio and increased urine flow rate,
29 days
24 days \
/
\
2 ! died
29 alive
142%)
*-~~~~^
8 Microinjection
158%! ^ - - » .
1
19 Clearances
/
2 Pressures
\
12 PAH
+ inulin
7 Inulin I
J
/ \
10 Inulin F/P ratio
single-nephron GFR
4 Pressures
FIG. 1. Fate of 50 female Sprague-Dawley rats subjected to
high bile-duct ligation and section. PAH, p-Aminohippurate;
GFR, glomerularfiltrationrate; F/P ratio,fluid/plasmaratio.
without a significant alteration in glomerular
filtration rate, electrolyte excretion rate or blood
pressure. Surprisingly, however, renal plasma flow,
renal blood flow and CPAH were all significantly
increased over control values. As a result wholekidney filtration fraction was markedly reduced in
chronic obstructive jaundice. EPAH did not differ
significantly.
Micropuncture studies
Superficial single-nephron glomerular filtration
rate was not significantly different in the jaundiced
and control rats (Table 3) whereas calculated
glomerular capillary hydrostatic presure (Pg) was
significantly higher in the jaundiced group. There
was a wide range of single-nephron glomerular
filtration rate values in each group, but the absolute
reabsorption rate in each nephron was closely
correlated with that nephron's filtration rate, that
is, each nephron showed a close degree of
glomerulotubular balance. Mean late proximal
(fluid/plasma) ratio, calculated on a per rat basis,
was not significantly different in the jaundiced and
control rats (jaundiced: 1-86 ± 0-36, n — 10;
control: 2-06 ± 0.34, n = 8).
Measurements of inulin (fluid/plasma) ratio were
also made at different points in the proximal
convoluted tubule. In Fig. 2 these have been plotted
against the loop number, determined as described
in the Methods section. The slope of the regression
line for both control and jaundiced animals results
is statistically significant, but the lines do not differ
significantly from each other.
The distribution of proximal intratubular hydro­
static pressure was not markedly different in
animals with obstructive jaundice (Fig. 3).
N.S.
34-5
±17
±9
N.S.
24-1
0-9178
±0152
N.S.
0-8396
±0174
N.S.
0-8633
±0105
43-0
±8-7
N.S.
45-3
±3-0
<0-005
48-4
+2-4
(%)
Packed cell
volume
7-3
±2-2
N.S.
6-9
±2-2
<0-005
4-1
±1-0
Urea
(mmol/1)
TABLE 2. Clearance data (left kidney) injaundiced rats and in sham-operated control rats
16-398
+4-60
<0-025
13-280
+4-14
<0-00I
7-000
+0-80
209
±35
N.S.
202
±34
<0025
238
±35
±11
29-3
Kidney wt.
(g)
6-49
±1-4
N.S.
6-70
±1-0
N.S.
6-5
±0-9
Plasma
protein
(g/100 ml)
111-5
±68-1
N.S.
80-4
±54-7
<0-005
7-01
±3-4
Serum
bilirubin
(^mol/1)
Jaundiced rats
(«=12)
P
Control rats
(n =15)
2-95
+ 1-22
<0-05
1-99
+0-77
Urine
flow rate
Oll min-1
g"1 of kidney)
247
+ 112
<0-05
344
+97
Inuiin
UIP
ratio
0-639
+0-174
N.S.
0-643
+0-2J
GFR
(ml min~l
l
g~ of kidney)
4-153
±1-31
<0-02
2-935
±1-08
RPF
(ml min"1
g~' of kidney)
0-17
+0-06
<0-005
•0-24
±0-03
FF
3-255
+0-67
<0-001
7-086
+0-79
-1
r
(ml min-1
g of kidney)
0-755
+008
NJS.
0-788
+0-069
7-342
+2-42
<0<05
5-474
+1-754
RBF
(ml min-1
g of kidney)
-1
0-2567
+0-2792
HS.
01353
+0-119
Sodium
excretion
Orniol min-1
g -1 of kidney)
0-5614
±2529
N.S.
0-5101
±0-347
Potassium
excretion
Oimdmin-1
-1
g of kidney)
98-3
+12-6
N.S.
102-1
±12-4
Blood
pressure
(mmHg)
Mean values ± SD are shown. N.S., Not significant. GFR, Glomerular filtration rate; RPF, renal plasma flow; FF, filtration fraction; C, clearance; E, extraction; PAH, p-aminohippurate;
RBF, renal blood flow.
Jaundiced rats
Died (n = 21)
P
Surviving rats
(n = 29)
P
Control rats
(n=15)
Liver wL
(g)
Body wt.
(g>
Days after
tie
Mean values + SD are shown. N.S., Not significant.
l ABLE i. uenerai cnaractertsucs of ou rats mm cnromc bile-duct ligaiion compared with those of15 sham-operated control rats
I
2
δ'
»
>3
M. E.M.Allison et al.
654
TABLE 3. Whole-kidney and single-nephron glomerular filtration rate and
calculated glomerular capillary hydrostatic pressure (P,) in jaundiced and
control rats
Mean values ± SD are shown N.S., Not significant. GFR, Glomerular filtration rate.
Jaundiced rats
(n = 10)
P
Control rats
(n=H)
GFR
(ml min"'
g~' of kidney)
Single-nephron
GFR
(nl/min)
Pg
(mmHg)
0-697 ± 0-17
18-8 ± 5-5
55-1 +5-0
N.S.
0-660 ±0-15
N.S.
19-5 ±6-2
<0025
49-6 ±4-5
3 0
0
1
2
3
4
5
6
7+8
Loop no.
Fio. 2. Inulin (fluid/plasma) ratio in different loops (nos. 1-9) of the proximal convoluted tubule in control (O)
and jaundiced ( · - - - # ) rats. Loop position was determined by visual observation of an injected oil droplet.
Loops no. 7 and no. 8 represent the late proximal convolution, as determined by the injection of lissamine green.
Control rats: r = 0-59, P < 0-01; jaundiced rats: r = 0-61, P < 001.
However, a very small number of nephrons with
raised hydrostatic pressure (up to 34 mmHg) were
found in all jaundiced rats examined. Mean intratubular hydrostatic pressure was significantly
higher in the jaundiced rats (jaundice: 16-7 ± 2-4
mmHg, n = 6; control: 12-4 +1-0 mmHg, n = 11,
P< 0-001).
There was no evidence of a significant transtubular leak of [3H]methoxyinulin in either group,
the percentage of microinjected inulin recovered
from the left kidney being 93-5 ± 3-7% (n = 7) in
obstructive jaundice and 98-4 ± 7-0% (n = 14) in
control rats.
Choledochoduodenostomy was carried out 1328 days after bile-duct ligation and the rats were
studied 12-28 days thereafter. Complete relief of
obstructive jaundice occurred in four out of eight of
the animals in which this was attempted, with a
resultant fall in serum bilirubin to 6-32 ±2-74
μπιοΐ/ΐ and a return of liver weight to values not
significantly different from control. In these rats
plasma urea concentration, packed cell volume,
renal plasma flow and filtration fraction were not
significantly different from the values in control
animals (Table 4).
In the remainder only partial relief of obstructive
Rena Ifunction in obstructive jaundice
jaundice was obtained, as judged by mildly
elevated bilirubin concentration, a continuing
elevation of blood urea, and moderate elevation of
liver weight.
Histology
Light-microscopy of the kidneys from rats with
obstructive jaundice revealed pigmented granules in
glomeruli, tubules and tubular casts. The Bow­
man's space of many of the glomeruli contained
granular debris. Mild degenerative changes with
focal dilatation were seen in some of the proximal
convoluted tubules.
Electron microscopy
Immersion fixation studies of the kidneys of rats
with obstructive jaundice revealed reproducible and
definite changes in the glomeruli 20-30 days after
obstruction (Fig. 4 and Fig. 5). The most striking
abnormality was the evidence of increased activity
of both epithelial and endothelial cells, which
showed increased density of the cytoplasm, closely
packed organelles and a rough endoplasmic
reticulum. The basement membrane appeared
muddy and the three layers were not clearly
delineated.
655
severely hypotensive and died either before or
during preparation for micropuncture. Only 20%
of the rats developed ascites, a much lower
incidence than reported by Bank & Aynedjian
(1975) and Yarger (1976) in studies on male
Sprague-Dawley rats. However, in earlier studies
in rats and dogs ascites was a late and inconstant
development (Gliedman et al, 1970; Mulland &
Gliedman, 1970; Better & Massry, 1972). These
differences may be related to variations in sodium
intake, as our animals took only about 60% of their
pre-operative sodium intake whereas those of Bank
& Aynedjian (1975) and Yarger (1976) continued
on a fixed sodium intake.
Definite, reproducible and reversible changes in
renal function were detected after 3-4 weeks of
total biliary tract occlusion. Whole-kidney
glomerular filtration rate,
single-nephron
glomerular filtration rate and afferent arteriolar
oncotic pressure were not significantly different in
the jaundiced and control groups of rats. Two other
factors determining glomerular filtration rate (i.e.
30
H 20
Discussion
Obstructive jaundice is simply produced in the rat
and its effects on liver structure and function are
well recognized (Cameron & Oakley, 1932;
Cameron & Hasan, 1958; Sasaki, 1960; Ryan et
ah, 1977). The mortality rate in experimental
obstructive jaundice is about 35% [Sasaki (1960)
and C. J. Ryan (personal communication)]. In the
present study 42% of the jaundiced rats became
5
10
15
20
25
30
Fio. 3. Distribution of proximal intratubular free-flow
hydrostatic pressure (mmHg) in six rats with obstructive
jaundice (stippled blocks) and 11 age-matched sham-operated
control rats (open blocks).
TABLE 4. mjfecl of complete relief of obstructive jaundice on plasma urea concentration, renal
plasmaflowandfiltrationfraction
Mean values + SD are shown. N.S., Not significant.
Choledochoduodenostomy
(n = 4)
P
Control rats
(« = 15)
P
Jaundiced rats
(« = 12)
35
Proximal intratubular pressure (mmHg)
Plasma urea
(mmol/1)
Renal plasma flow
(ml min-1
g -1 of kidney)
Filtration
fraction
4-4
3·59±0·5
0·22 ± 0·02
N.S.
4-1 + 1-0
N.S.
2-94 ± 1-1
N.S.
0-24 + 0·03
<0·005
7-0 ± 2-8
<002
4-15 + 1-31
<0·005
0-17 ±0-06
656
M. E. M. Allison et al.
FIG. 4. Electron micrograph (original x 17 500) of glomerulus from sham-operated control rat. The three layers of
the basement membrane are clearly delineated and the epithelial and endothelial cells appear quite normal with no
evidence of increased cytoplasmic activity. The normal fenestrated endothelial configuration is clearly visible, as
are the epithelial foot processes.
Pt and proximal intratubular hydrostatic pressure),
although significantly different in the two groups,
cancel each other out. However, there is an
increase in whole-kidney renal plasma flow and
hence renal blood flow, calculated from the
clearance and extraction of p-aminohippurate in
the jaundiced group. As a result whole-kidney
filtration was significantly reduced in obstructive
jaundice. In previous studies there has been a fall in
total renal plasma flow (Gliedman et al., 1970;
Bank & Aynedjian, 1975; Yarger, 1976) with
evidence of redistribution of flow from cortex to
inner medulla (Yarger, 1976).
However, there are two reasons why we believe
Renalfunction in obstructive jaundice
657
-*■/,*■
Vl^rfr"'
FIG. 5. Electron micrograph (original x 17 500) of a glomerulus from a rat with obstructive jaundice. There is an
increase in activity of both epithelial and endothelial cells, with marked endothelial cell swelling. The basement
membrane appears muddy and the three layers are not clearly delineated.
that there was a rise in renal plasma flow in our
jaundiced rats. First, the increase in renal plasma
flow disappeared on successful reversal of the
obstructive
jaundice
by
choledochoduodenostomy. Secondly, calculation of the renal
plasma flow by the clearance and extraction of
inulin, rather than p-aminohippurate, also showed
renal plasma flow to be significantly increased in
obstructive jaundice. Inulin is excreted solely by a
process of glomerular ultrafiltration (Gutman,
Gottschalk & Lassiter, 1965) and there was no
evidence of increased transtubular permeability to
inulin in the jaundiced rats. The structural changes
we observed in the glomeruli were very similar to
those reported by Sakaguchi et al. (1965) and
Arhelger et al. (1970). It is interesting that similar
M. E.M.Allison
658
changes have recently been reported by others in
the early stages of acute renal failure from the
intrarenal infusion of noradrenaline (Cox, Baehler,
Sharma, O'Dorisio, Osgood, Stein & Ferris, 1974;
Stein & Sorkin, 1976), angiotensin (Hornych,
Beaufils & Richet, 1972) or uranyl nitrate (Stein,
Gottschalk, Osgood & Ferris, 1975). However,
others have been unable to confirm these findings
(Blantz, 1975). It is possible, however, that the fall
in filtration fraction which we observed might
reflect a decrease in glomerular permeability in
obstructive jaundice.
In contrast to two recent kidney micropuncture
studies (Bank & Aynedjian, 1975; Yarger, 1976),
we found no significant change in fractional or
absolute reabsorptive rate in the proximal con­
voluted tubule in the jaundiced rats. However, none
of our animals had ascites whereas this was a
prominent feature in the previous studies.
Although there was no change in proximal
tubular reabsorption there must have been a
reduced reabsorption at more distal sites as the
jaundiced rats had a significantly raised urine flow
rate and reduction in inulin (urine/plasma) ratio. In
fact urine osmolality fell significantly within 24 h of
bile-duct obstruction, despite no increase in water
intake in comparison with control rats, and this
could be due to a decreased concentrating ability.
A marked fall in urinary concentrating ability in
dogs with chronic obstructive jaundice was
described by Better & Massry (1972) and ascribed
to a fall in sodium content of the inner medulla and
a fall in protein consumption. Unconjugated
bilirubin was later shown to be a cause of the fall in
urinary concentrating ability in the Gunn strain of
rats, which lack hepatic glucuronyl transferase
(Call & Tisher, 1975).
Nearly half our jaundiced rats died before
precise renal function studies could be made. Our
observations of subtle but consistent changes in
glomerular structure and function and in tubular
function apply, therefore, only to the hardy
survivors. The cause of these changes and the
reason for the high mortality rate remains
unknown.
Acknowledgments
This study was supported by MRC grant
G972/527/C
and
by
S.H.H.D.
grant
K/MRS/32/C5.
References
et al.
ALLISON,
M.E.M.,
LIPHAM,
E.M.,
LASSITER,
W.E.
&
GOTTSCHALK, C.W. (1973) The acutely reduced kidney.
Kidney International, 3.354-363.
ALLISON, M.E.M., WILSON, C.B. & GOTTSCHALK, C.W. (1974)
Pathophysiology of experimental glomerulonephritis in rats.
Journal of Clinical Investigation, 53,1402-1423.
ARENDSHORST,
W.J.,
FINN,
W.F.
&
GOTTSCHALK,
C.W.
(1975) The pathogenesis of acute renal failure following
temporary renal ischaemia in the rat. Circulation Research,
37, 558-568.
ARHELGER, R.B., DAVIS, J.T., EVERS, C G . , HENSON, E.C. &
HARDY, J.D. (1970) Experimental cholemia in dogs. Archives
of Pathology, 89,355-363.
AYER, D. (1938) Renal lesions associated with deep jaundice.
Archives of Pathology, 22,26-41.
BANK, N. & AYNEDJIAN, H.S. (1975) A micropuncture study of
renal salt and water retention in chronic bile duct obstruction.
Journal of Clinical Investigation, 55,994-1003.
BETTER, O.S. & MASSRY, S.G. (1972) Effect of chronic bile
duct obstruction on renal handling of salt and water. Journal
of Clinical Investigation, 51,402-411.
BLANTZ, R.C. (1975) The mechanism of acute renal failure after
uranyl nitrate. Journal of Clinical Investigation, 55, 6 2 1 635.
BRAYSHAW, B.J. (1971) Manual and automated techniques for
total and conjugated bilirubin. Medical
Laboratory
Techniques, 28,133-140.
BRENNER,
B.M.,
FALCHUK,
K.H.,
KEIMOWITZ,
R.D.
&
BERLINER, R.W. (1969) The relationship between peritubular
capillary protein concentration and fluid reabsorption by the
renal proximal tubule. Journal of Clinical Investigation, 48,
1519-1531..
CALL, N.B. & TISHER, C.C. (1975) The urinary concentrating
defect in the Gunn strain of rat. Journal of Clinical
Investigation, 55,319-329.
CAMERON, G.R. & HASAN, S.M. (1958) Disturbances of
structure and function in the liver as a result of biliary
obstruction. Journal of Pathology and Bacteriology, 75,333—
349.
CAMERON, G.R. & OAKLEY, C.L. (1932) Ligation of the
common bile duct. Journal of Pathology and Bacteriology,
35,769-798.
CATTELL, W.R. & BIRNSTINGL, M. (1964) Surgical Research
Society. Renal function in obstructive jaundice. British
Journal of Surgery, 51,72-73.
CLAIRMONT, P. & VON HABERER, Η. (1911) Mitteilungen aus
den Grenzegebeiten de Medizin und Chirurgie, 22,159-172.
Cox, J.W., BAEHLER, R.W., SHARMA, H., O'DORISIO, T.,
OSGOOD, R.W., STEIN, J.H. & FERRIS, J.H. (1974) Studies
on the mechanism of oliguria in a model of unilateral renal
failure. Journal of Clinical Investigation, 53,1546-1558.
DAWSON, J.L. (1965a) The incidence of postoperative renal
failure in obstructive jaundice. British Journal of Surgery, 52,
663-665.
DAWSON, J.L. (1965b) Post-operative renal function in obstruc­
tive jaundice: effect of a mannitol diuresis. British Medical
Journal, i, 82-86.
DAWSON, J.L. (1968) Acute post-operative renal failure in
obstructive jaundice. Annals of Royal College of Surgeons of
England, 42,163-181.
ELSOM, K.A. (1937) Renal function in obstructive jaundice.
Archives of Internal Medicine, 60, 1028-1033.
FAJERS, C M . (1957) Experimental studies on cholemic
nephrosis. Acta Pathologica et Microbiologica Scandinavica,
41,44-55.
FAWCETT, J.K. & SCOTT, J.E. (1960) A rapid and precise
method for the determination of urea. Journal of Clinical
Pathology, 13,156-159.
C.W.
FUNCK-BRENTANO, J.L., MERY, J.P., VANTELON, J. & WATCHI,
(1972) Hydrostatic pressure in the rat kidney. American
Journal of Physiology, 223,975-983.
J. (1963) Les insuffisances renales aigue de l'angiocholite
uremigene (18 observations personelles). La Presse Medicate,
71,1039-1042.
ALLISON,
M.E.M.,
LIPHAM,
E.M.
&
GOTTSCHALK,
Renalfunction in obstructive jaundice
GLIEDMAN, MX., CARROLL, H J . , POPOWITZ, L. & MULLANE,
J.F. (1970) An experimental hepatorenal syndrome. Surgery,
Gynecology and Obstetrics, 131,34-40.
GOTTSCHALK, C.W., MOREL, F . & MYLLE, M. (1965) Tracer
microinjection studies of renal tubular permeability.
American Journal of Physiology, 209,173-178.
GOTTSCHALK, C.W. & MYLLE, M. (1956) Micropuncture study
of pressures in proximal tubules and peritubular capillaries of
the rat kidney and their relation to ureteral and venous
pressures. American Journal of Physiology, 185,430-439.
GUTMAN, Y., GOTTSCHALK, C.W. & LASSITER, W.E. (1965)
Micropuncture study of inulin absorption in the rat kidney.
Science, 147,753-754.
HELWIG, F.C. & SCHUTZ, C.B. (1932) A liver kidney syndrome.
Surgery, Gynecology and Obstetrics, 55,570-580.
HEYD, C G . (1931) Liver deaths in surgery of the gallbladder.
Journal of the American Medical Association, 97, 1847—
1854.
HORNYCH, H., BEAUFILS, M. & RICHET, G. (1972) The effect of
exogenous angiotensin on superficial and deep glomeruli in
the rat kidney. Kidney International, 2,336-343.
LANDIS, E.M. & PAPPENHEIMER, J.R. (1963) Exchange of
substances through capillary walls, In: Handbook of Physio­
logy, Circulation, section 2, vol. 11, chapter 29, pp. 9 6 1 1034. American Physiology Society, Washington, D.C.
LEE, E. (1972) The effect of obstructive jaundice on the
migration of retroblasts into early experimental granulomata.
British Journal of Surgery, 59,875-877.
MAROSKE, D., BICHLER, K.H., NABER, K., H U P E , K., MÜLLER,
K.H., OBROWSKI, I., SCHREIBER, H.U. & H A A S , J. (1971)
Der komplette extrahepatische Verschlubikterus. Tierexperi­
mentelle Untersuchungen am Hund. Bruns' Beitrage zur
Klinischen Chirurgie, 219,166-178.
MULLANE, J.F. & GLIEDMAN, M.L. (1970) Renal response to
saline load in experimental liver disease. Journal of Surgical
Research, 10,519-523.
659
POPPER, H. & SCHAFFNER, F. (1957) Liver: Structure and
Function. McGraw Hill Book Co. Inc., Blakiston.
RAVDIN, I.S. (1929) Vasodepressor substance in the liver.
Archives of Surgery, 18,2191-2201.
RYAN, C.J., T H A N T H A N & BLUMGART, L.H. (1977) Chole-
dochoduodenostony in the rat with obstructive jaundice.
Journal of Surgical Research, 23,321-331.
SAKAGUCHI, H., D A C H S , S., GRISHAM, E. & CHURG, J. (1965)
Renal glomerulus in obstructive jaundice. Archives of
Pathology, 79,512-517.
SASAKI, H. (1960) Experimental obstructive jaundice in rats.
Morphogenetic studies on biliary cirrhosis. Ada Medica
University Kioto, 37,59-83.
S0RENSEN,
F.H.,
ANDERSON,
J.B.
0RNSHOLT,
J.
&
SKJOLDBORG, H. (1971) Acute renal failure complicating
biliary tract disorders. Ada Chirurgica Scandinavica, 137,
87-91.
STEIN, J.H., GOTTSCHALK, J., OSGOOD, R.W. & FERRIS, T.F.
(1975) Pathophysiology of a nepnrotoxic model of acute
renal failure. Kidney International, 8,27-41.
STEIN, J.H. & SORKIN, M.I. (1976) Pathophysiology of a
vasomotor and nephrotoxic model of acute renal failure in the
dog. Kidney International, 10, S-86-S-93.
WILBUR, O.L. (1934) The renal glomerulus in various forms of
nephrosis. Archives of Pathology, 18,157-185.
WILLIAMS, R.D., ELLIOT, D.W. & ZOLLINGER, R.W. (1960)
The effect of hypotension in obstructive jaundice. Archives of
Surgery, 81,335-340.
WRIGHT, J.E. & BRAITHWAITE, J.L. (1962) Collateral biliary
channels. Nature (London), 195,95-96.
YARGER, W.E. (1976) Intrarenal mechanisms of salt retention
after bile duct ligation in rats. Journal of Clinical
Investigation, 57,408-418.