Increased incidence of glomerulonephritis following spleno-renal shunt surgery in non-cirrhotic portal fibrosis. In a prospective study of 200 non-cirrhotic portal fibrosis (NCPF) patients, 7% had mild proteinuria and their renal biopsies showed mild mesangial proliferative glomerulonephritis (mes-PGN). The remaining 93% biopsies were normal. However, following the insertion of a spleno-renal shunt (SRS) for portal hypertension 32% of these patients developed nephrotic syndrome in five years. Renal histology revealed mesangiocapillary glomerulonephritis (MCGN) (18.5%), mes-PGN (9%), minimal change nephropathy (3%), and chronic sclerosing GN (1.5%). Immunofluorescence showed granular deposition of IgA and C3. IgA2 was the predominant form of Ig in the glomerular deposits, indicating that IgA in the immune complexes was derived from the gastrointestinal tract. Electron microscopy revealed electron dense deposits in the mesangium. In contrast to the NCPF patients who underwent a SRS for portal hypertension, the 200 patients in our study who underwent spleno-renal shunting because of extra hepatic portal obstruction did not have renal disease, nor did they develop renal disease during the five-year post-operative follow-up. Fifty percent of the glomerulonephritis (GN) in the NCPF group progressed to renal failure in five years; 46.6% continued to have proteinuria. Low serum complement, C3 (40%) and circulating immune complexes (14.8%) were detected in the glomerulonephritis group. Our study shows that: (i) there is a high rate of the occurrence of GN following SRS in NCPF patients, but not in those with normal livers; (ii) the type of GN is primarily IgA nephropathy; and (iii) the GN could be the result of defective hepatic reticuloendothelial function in the NCPF group that is worsened by the shunting procedure

Agarwal, Sanjay K.

Bhuyan, Uday N.

Dash, Suresh C.

Dinda, Amit K.

Nundy, Samiran

Saxena, Sanjiv

Tiwari, Suresh C.

Elsevier - Publisher Connector 

Increased incidence of glomerulonephritis following spleno-renal shunt surgery in non-cirrhotic portal fibrosis 

Kidney International, Vol. 52 (1997), pp. 482—485
Increased incidence of glomerulonephritis following spleno-renal
shunt surgery in non-cirrhotic portal fibrosis
SURESH C. DASH, UDAY N. BHUYAN, AMIT K. DINDA, SANJIV SAXENA, SANJAY K. AGARWAL,
SURESH C. TIwMU, and SAJ\nR&N NUNDY
Departments of Nephrology, Pathology and Gastrointestinal Surgety, All India Institute of Medical Sciences, New Delhi, India
Increased incidence of glomerulonephritis following spleno-renal shunt
surgery in non-cirrhotic portal fibrosis. In a prospective study of 200
non-cirrhotic portal fibrosis (NCPF) patients, 7% had mild proteinuria
and their renal biopsies showed mild mesangial proliferative glomerulo-
nephritis (mes-PGN). The remaining 93% biopsies were normal. How-
ever, following the insertion of a spleno-renal shunt (SRS) for portal
hypertension 32% of these patients developed nephrotic syndrome in five
years. Renal histology revealed mesangiocapillary glomerulonephritis
(MCGN) (18.5%), mes-PGN (9%), minimal change nephropathy (3%),
and chronic sclerosing GN (1.5%). Immunofluorescence showed granular
deposition of IgA and C3. IgA2 was the predominant form of Ig in the
glomerular deposits, indicating that IgA in the immune complexes was
derived from the gastrointestinal tract. Electron microscopy revealed
electron dense deposits in the mesangium. In contrast to the NCPF
patients who underwent a SRS for portal hypertension, the 200 patients in
our study who underwent spleno-renal shunting because of extra hepatic
portal obstruction did not have renal disease, nor did they develop renal
disease during the five-year post-operative follow-up. Fifty percent of the
glomerulonephritis (GN) in the NCPF group progressed to renal failure in
five years; 46.6% continued to have proteinuria. Low serum complement,
C3 (40%) and circulating immune complexes (14.8%) were detected in the
glomerulonephritis group. Our study shows that: (i) there is a high rate of
the occurrence of GN following SRS in NCPF patients, but not in those
with normal livers; (ii) the type of GN is primarily IgA nephropathy; and
(iii) the GN could be the result of defective hepatic reticuloendothelial
function in the NCPF group that is worsened by the shunting procedure.
Nearly 25 to 30% of all patients with portal hypertension in
India who undergo surgery or scierotherapy have non-cirrhotic
portal fibrosis (NCPF) [1, 2]. The majority of these patients come
from a lower or middle socioeconomic background, and variceal
bleeding is the most common presenting feature. The spleno-
renal shunt (SRS) has been found to be quite useful in controlling
variceal hemorrhage. The disease seems to have a protracted
benign course with good prognosis following the insertion of the
SRS [31. However, glomerulonephritis has been reported in
patients with NCPF particularly following SRS surgery [4, 5]. In
the present study, we prospectively determined the prevalence
Key words: glomerulonephritis, shunt surgery, fibrosis, nephrotic syn-
drome, hypertension, cirrhosis.
Received for publication July 1, 1996
and in revised form March 5, 1997
Accepted for publication March 6, 1997
© 1997 by the International Society of Nephrology
and characteristics of glomerular changes in patients with NCPF
and the relationships of these renal lesions with portal hyperten-
sion and the SRS procedure.
METHODS
Two hundred consecutive, (earlier) biopsy-proven patients with
NCPF and 200 with extra-hepatic portal obstruction (EHPO)
admitted for the proximal SRS procedure were investigated. The
cause of EHPO was portal vein thrombosis during childhood, a
well-recognized condition in India. Alcoholism, systemic infection
before or after surgery, and nephrotoxic drug therapy were
criteria for exclusion. An episode of a major bleed from esopha-
geal varices due to portal hypertension was the main indication for
the SRS procedure. Each patient underwent splenectomy and
anastomosis of splenic vein to the left renal vein, allowing part of
portal circulation to directly enter the renal vein and then into the
inferior vena cava. In this way the shunt decreased portal hyper-
tension and increased portosystemic shunting. The mean age of
NCPF patients was 28 years (range 14 to 44 years) and of EHPO
patients was 19 years (range 9 to 23 years) with a male:female
ratio of 3.1:1 and 6:1, respectively. The investigations routinely
carried out in all the subjects included: liver function tests,
hepatitis B virus (HBsAg) by radioimmunoassay, hemoglobin,
total leukocyte and differential counts, reticulocyte and platelet
counts, and eiythrocyte sedimentation rate.
Serum complement C3 and circulating immune complexes were
determined by the polyethylene glycol precipitation procedure [6].
Blood for cryoglobulinemia and anti—HCV (hepatitis C) were
tested in those who developed GN during the post-operative
period.
Renal function studies included routine urinalysis, 24-hour
urinary protein estimation (by the Diacetyl monoxime method),
blood urea, creatinine (using an Auto Analyzer; Medical System
Polystat 2000) and creatinine clearance.
Following the necessary ethical approval and individual pa-
tient's consent, an intraoperative left renal biopsy was taken
before splenectomy and spleno-renal shunting. There were no
complications. Specimens were subjected to light microscopic
(LM), immunofluorescence (IF) and electronmicroscopic (EM)
examinations. In addition to the physical examination, the post-
operative follow-up included urinalysis, and a biochemical assess-
ment of renal, hepatic and hematologic functions every six
months. Repeat percutaneous renal biopsies were performed in
482
Dash et a!: GN triggered by spleno-renal shunt 483
Table 1. Renal function data in non-cirrhotic portal fibrosis before and after splenorenal shunting operation in 200 patients
Pre-operative
Post-operative
1 Month 1 Year 2 Years 3 Years 4 Years 5 Years
Proteinuria % of patients having > 300 mg/24 hrs 7 8.5 11.5 26 27.5 29 32
Mean Upr >< V g/24 hr
M = 0.56 0.09 0.6 0.13 1.1 0.28 2.5 0.45 3.5 0.46 3.8 0.51 3.6 0.56
N = 14 17 23 52 55 58 64
Hematuria % 200 patients 0 6 18 18 20 25 22
Average Cr (m1/month)'M = 79 14 61 5.0 60 8.0 48 9.0 41 12 38 16 32 14
N = 14 17 23 52 55 58 64
Serum creatinine mg/dl 1.0 0.1 1.0 0.3 1.4 0.4 1.5 0.4 2.7 1.4 2.8 1.6 3.3 1.7
Abbreviations are: Car, creatinine clearance; M, mean value; N, number of patients.
a In patients who developed glomerulonephritis.
all those who developed significant proteinuria during the fol-
low-up period.
Histological studies
Specimens were fixed in neutral buffered formalin and after
processing, 3 j.tm paraffin sections were stained with hematoxylin-
eosin (HE) and periodic acid-Schiff (PAS), silver methenamine
(SM) and Maritus scarlet blue for light microscopical examina-
tion. A minimum of six glomeruli were taken as criteria for
adequate biopsy.
Renal tissue for IF was available in 205 cases (122 NCPF, 83
EHPO). Tissue was snap-frozen and cut in Cryostat into 5 to 6 jm
thick sections. The sections were stained with fluorescent mono-
specific antisera (Welicome Reagents, UK) to demonstrate de-
posits of IgA, IgG, 1gM, complement (C3) and fibrinogen—fibrin
(Fi). In addition, frozen sections of the biopsies of 10 patients with
NCPF who developed GN during the post-operative follow-up
were stained for JgGAI and IgA2 and examined under an IF
microscope. Similarly, 20 random biopsies from NCPF patients
where light microscopy and IF showed mesangial hypercellularity
or immune deposits were processed for the EM study. Five
random samples from EHPO were taken for comparison. Small
cubes of renal tissue were fixed in buffered glutaraldehyde for
EM.
RESULTS
Renal function studies
There were no immediate post-operative complications and
patients remained free of hematemesis during the follow-up
period.
In the NCPF group, the incidence of proteinuria (UprV)
increased from 7% during the pre-operative period to 32% during
the post-operative follow-up (Table 1). Twenty-eight percent of
these clinically presented as nephrotic syndrome (mean UprV =
3.6 g) in five years. Microhematuria increased from 6% at one
month post-operatively to 25% after four years. Pre-operative
average serum creatinine of 1.0 0.1 mg% in the 64 patients who
developed glomerulonephritis following SRS operation increased
progressively to 3.3 1.7 mg% at five years, and creatinine
clearance progressively declined to 32 14 ml/minute during the
corresponding period (Table 1). In EHPO patients no significant
proteinuria (defined as > 300 mg in 24 hr) and/or hematuria were
observed; the prevalence of significant proteinuria in the general
Indian population is 0.01%. Renal biopsy showed mild mesangial
Fig. 1. Mesangiocapillary glomerulonephritis showing thickening of cap-
illary walls, hypercellularity and lobular formation following the Leino
renal shunting operation (hemaloxylin and eosin stain, X200).
proliferation in 3 (1.5%) EHPO patients that did not progress
during the follow-up period.
Renal biopsy (light microscopy)
Light microscopy revealed GN in 32% of NCPF patients,
mesangiocapillary GN in 18.5% (Fig. 1), mesangial proliferative
GN in 9% (Fig. 2), minimal change disease in 3%, and chronic
sclerosing GN in 1.5%. One third of the patients with mesangio-
capillaty GN and 1/5 with mesangial PGN showed varying degrees
of extra-capillary crescents.
Immunofluorescence
Glomerular mesangium was strongly positive for granular IgA
and C3 (Fig. 3) deposition in 52%. In 47% there was mixed
deposition of IgA, C3 and weakly positive 1gM. All 10 tissue
samples stained against IgA1 and IgA2 were positive for the latter
and negative for the former. This finding suggested that the
immunoglobulins were derived from gastrointestinal tract. Capil-
lary walls did not reveal any deposits. Fibrin was detectable only
where crescents were found. Mesangial IgA, C3 and 1gM deposits
corresponded to diffuse mesangial proliferation seen on light
microscopy.
484 Dash et al: GN triggered by spleno-renal shunt
Fig. 2. Mesangioproliferative glomerulonephritis showing mesangial ex-
pansion with increased hypercellularity (hematoxylin and eosin stain,
x200).
Fig. 4. Electron photomicrograph showing electron dense deposit in the
mesangial cell cytoplasm (x4200).
group, respectively. Cryoglobulins were negative in the serum of
all those who developed GN. In the liver function tests hypoalbu-
minemia was the only abnormality observed in both groups, and
the remaining parameters were normal (Table 2).
Outcome
At the end of five years the average GFR fell from pre-
operating value of 79 14 mI/mm to 32 14 mI/mm in 58% of
the GN patients, 50% of whom showed elevated blood urea
nitrogen. In 46.6%, proteinuria continued while 3% remained
free of proteinuria.
DISCUSSION
Fig. 3. Granular deposits of IgA in the mesangium (fluorescent antihu-
man IgA, x350).
Electron microscopy
In 25 patients with NCPF there were electron dense deposits
that looked discrete, granular and were confined to the mesan-
gium, the capillary walls being free of any deposit (Fig. 4).
Mesangial cells were increased in number whereas the endothelial
cells were unremarkable. These features corresponded to the
mesangial cell proliferation seen on LM and IgA and C3 deposits.
In one patient with EHPO, faint mesangial deposits were de-
tected.
Hematological and immunological observations
Patients with NCPF tended to have lower leukocyte and
platelet counts than patients with EHPO, which improved follow-
ing splenectomy and the SRS operation (Table 2). Serum com-
plement (C3) and circulating immune complexes (CIC) were
positive in 40% and 14.8%, respectively in NCPF; these were
negative in EHPO patients. Hepatitis B and anti—HCV were
positive in 18% and 12% of the NCPF group, respectively, but
neither of these markers correlated with the occurrence of GN.
HBsAg and anti—HCV were detected in 7% and 6% of the EHPO
We found that in NCPF patients, there was another 25%
increase in the incidence of GN within five years following the
SRS operation. More accurately it was IgA nephropathy in the
most patients, with 27.5% showing MCGN and mesangial PGN
apearance on light microscopy. IgA was the dominant immuno-
globulin deposited along with C3 in granular pattern indicating
an immune complex type of GN. The demonstration of electron
dense deposits in the mesangium suggested immune com-
plexes and not mere trapping of IgA in the glomeruli. Further,
in clinical terms NCPF patients presented a picture of nephrotic
syndrome with significant proteinuria. In contrast, none of the
El-IPO patients had significant proteinuria prior to or following
surgery.
Renal lesions have been described in cirrhotics for more than
25 years. These constituted a marked PAS positive thickening of
glomerular mesangium [7]. Fisher and Perez also described
mesangial PGN [8] with some correlation between the extent of
renal lesions and duration of cirrhosis. Callard et al reported that
granular deposits were mainly IgA and C3 [9]. However, such
lesions have not been described in NCPF following SRS surgery
thus far.
The pathogenesis of an increased occurrence of glomerulone-
phritis in NCPF patients following spleno-renal shunting is not
clear. In cirrhosis it has been related to presence of hepatitis B
surface antigen [10]. Although 18% of the NCPF patients in the
present study were positive for HBsAg and 12% for anti—HCV,
the development of GN was not related to these markers.
ta
 
ri  ngioproli ti l l ri i i  sangial e
i  it  i r  v rceltul rit  ( t li   i  tair
<20 .
Dash et al: GN triggered by spleno-renal shunt 485
Investigation
Hematological
Hemoglobin
TLC cells mm3
Platelet count
ESR mm/hr
Immunological %
Low serum C3
CIC +ve
Cryoglobulinemia
Liver Function Test
Serum bilirubin mg/dl
Albumin/globulin g/dl
SGOT/SGPT JU
SAP KU
HBsAg +ve %
HC5Ag +ve %
Pre-op
9.6 1.8
3900 1600
88000 22000
20
ND
ND
ND
0.6
2.6/3.7
32/38
10
18
ND
Post-op (1 month)
11.0 1.4
4800 1700
14000 17000
13
40
14.8
0
0.8
2.8/3.1
24/18
12
18
12
9.7 :t 1.5
4500 1300
130000 2000
14
ND
ND
ND
0.6
2.6/3.2
32/28
14
0
ND
10.9 1.8
5100 1600
130000 16000
12
0
0
0
0.8
3.6/3.2
24/20
13
7
6
Abbreviations are: ND, not done, C3, Complement C3; TLC, total leukocyte count; SAP, serum alkaline phosphatase.
Experimentally, saturation of the reticuloendothelial system
(RES) in mice with colloidal carbon together with oral immuni-
zation produces mesangial IgA deposition, and inhibition of
normal hepatic clearance mechanisms is probably the most im-
portant factor involved [Ii]. It is known that the function of
hepatic RES in NCPF is poor where in EHPO it is intact. The
spleno-renal shunt procedure is carried out to reduce portal
hypertension and thus prevent gastrointestinal hemorrage from
esophageal varices. However, the procedure enhances the direct
portosystemic circulation and partly bypasses hepatic RES. Pa-
tients with marginal hepatic reticuloendothelial function, the first
pass clearance of immune complexes emanating from the gastro-
intestinal tract is critical in preventing excessive levels of circulat-
ing immune complexes. When the first pass uptake of immune
complexes is eliminated, there is excessive delivery of pathogenic
immune complexes to the systemic circulation leading to immune
complex GN. Demonstration of IgG2 in glomerular mesangium
indicating that the IgA was derived from the gastrointestinal tract
provides supportive evidence to the hypothesis outlined above.
This hypothesis explains why there was increased incidence of GN
following SRS procedure in the present series. However, SRS in
EHPO patients with intact hepatic RES but not associated with
GN suggests that the spleno-renal shunting procedureperse is not
the predisposing factor, but it can be in the presence of poor
hepatic clearance, as in NCPF patients.
ACKNOWLEDGMENT
Part of the paper was presented at the 5th Asia Pacific Congress of
Nephrology held December 1992 in New Delhi, India.
Reprint requests to Suresh C. Dash, M.D., D.M., Department of Nephrol-
ogy, All India institute of Medical Sciences, New Delhi-i 10029, India.
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Table 2. Hematological, immunological and liver function data
NCPF EUPO
-
Pre-op Post-op (1 month)


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Increased incidence of glomerulonephritis following spleno-renal shunt surgery in non-cirrhotic portal fibrosis

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