‘Full house’ positive immunohistochemical membranoproliferative glomerulonephritis in a patient with portosystemic shunt

Alexander De Smet1, Dirk Kuypers1,, Pieter Evenepoel1, Bart Maes1, Thierry Messiaen1, Boudewijn Van Damme2 and Yves Vanrenterghem1

1 Department of Nephrology, Renal Transplantation and 2 Department of Pathology, University Hospitals Leuven, Belgium

Keywords: full house immunostaining; liver cirrhosis; membranoproliferative glomerulonephritis; nephrotic syndrome; portosystemic shunt



   Introduction
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 Introduction
 Case
 Discussion
 References
 
The term membranoproliferative glomerulonephritis is used to describe a well defined histological form of glomerulonephritis characterized by mesangial proliferation and thickening of the capillary wall due to interposition of mesangial cells. If no triggering mechanism is identified, it is called primary membranoproliferative glomerulonephritis. Three main types can be differentiated; types I, II, and III. A different pathogenesis is suspected but not yet elucidated. Idiopathic or primary type I membranoproliferative glomerulonephritis with subendothelial electron dense deposits and hypocomplementaemia is usually associated with an immune complex-mediated pathogenesis [1]. A similar histological image can be seen with underlying viral, bacterial and parasitic infections, and autoimmune disorders such as systemic lupus erythematosus: secondary membranoproliferative glomerulonephritis. Reports of membranoproliferative glomerulonephritis in patients with a portosystemic shunt have also been described [24]. A functional bypass of the hepatic reticuloendothelial system by the portosystemic shunt and consequently reduced clearance of immune complexes is thought to play a causative role. The fact that IgA2 complexes are normally transferred from the gastrointestinal wall into the portal circulation and the presence of IgA2 in renal biopsies of patients with portal shunt-related glomerulonephritis seems to support this hypothesis [2,3,5]. We present a case of membranoproliferative glomerulonephritis occurring 20 years after construction of a portosystemic shunt in a patient with idiopathic incomplete septal cirrhosis. Interestingly, the ‘full house’ positive immunostaining shows resemblance with lupus-associated membranoproliferative glomerulonephritis and has to our knowledge in this clinical setting never been reported in the literature.

The interpretation of this unique finding is discussed in view of the current hypothesis regarding the pathogenesis of membranoproliferative glomerulonephritis.



   Case
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 Introduction
 Case
 Discussion
 References
 
A 40-year-old male patient was referred to our centre for relapsing hepatic coma. In childhood, an unspecified congenital syndrome was diagnosed that comprised mental retardation, vitiligo, clumb feet, webbed neck, and aortic regurgitation. A specific genetic defect could not be identified with chromosomal analysis. At the age of 20 the diagnosis of liver cirrhosis was made following bleeding from oesophageal varices. The first liver biopsy revealed a histological picture of macronodular cirrhosis of the incomplete septal type. Because of severe portal hypertension a splenectomy was performed and a side-to-side portocaval shunt was constructed. In 1999, 20 years after construction of the shunt, the patient suddenly developed diffuse oedema with ascites. Episodes of hepatic coma occurred with increasing frequency. The patient was referred back to us for further therapeutic advice and for evaluation of the possibility of liver transplantation.

At the time of hospitalization clinical examination revealed the known features of his congenital syndrome, anasarc oedema, and massive ascites. A flapping tremor was absent, the Glasgow coma scale was 15/15. Laboratory test on admission are listed in Table 1Go.


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Table 1. Laboratory tests on admission

 
Severe renal failure and a nephrotic syndrome were diagnosed. Urine sediment microscopy identified dysmorphic haematuria and red blood cell casts. Kidney size assessed by renal ultrasound, was 13.5 cm for the left kidney and 14.5 cm for the right kidney; cortical thickness was normal.

Immunological screening including ANA, anti-dsDNA and ANCA (MPO and PR3) was repetitively negative. A low C3 level was measured once, although no further evidence for complement consumption was found. A very low titer of mixed cryoglobulines was measured once, but never confirmed by frequent control samples. Hepatitis B and C screenings were negative including hepatitis B DNA-PCR and hepatitis C RNA.

An angio-MRI of the liver showed a patent surgical portocaval shunt with normal centripetal flow.

A diagnostic renal biopsy was performed. Light microscopic examination showed mesangial proliferation and thickening of the capillary wall with splitting of the basement membrane (Figure 1Go). Immunohistochemistry marked intense mesangial and subendothelial deposition of complement (C3 and C1q) and all immunoglobulins (IgA, IgM, and IgG) (Figure 2Go). Mesangial deposition of an electron dense material with extension into the capillary wall and splitting of the basement membrane, was seen on electron microscopy. The histological diagnosis of a membranoproliferative glomerulonephritis type I with a ‘full house’ positive immunostaining was made.



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Fig. 1. Light microscopy of renal tissue showing membranoproliferative changes in a representative glomerulus; methenamine silver (x250).

 


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Fig. 2. Immunohistochemical demonstration of (a) C3, (b) IgA, (c) IgG, and (d) IgM in renal biopsy. In all pictures a representative positivity is shown. (c) The arrows point to deposits along the basement membrane. The staining for C1q shows a picture identical to that of IgM (all x60).

 
A thorough search for clinical and biochemical features of typical and atypical SLE (in association with complement deficiencies) was repeated but remained negative. Systemic sclerosis and mixed cryoglobulinaemia were excluded. Underlying malignancies were not found, serum alpha-1-anti-trypsine levels were normal as were the immunoglobulines and complement factors. An extensive screening for possible low-grade underlying infections remained negative.

A trial with high dose oral steroids was attempted without success. Efforts to control the nephrotic syndrome with diuretics and ultrafiltration failed and induced relapsing episodes of hepatic coma. The nephrotic syndrome was considered to be therapy-resistant and it was agreed that additional immunosuppressive therapy would jeopardize the patient's situation even further. As a final resort, the patient and his family agreed to a bilateral nephrectomy. Pathological examination of the nephrectomy specimen confirmed the initial histological diagnosis and the immmunohistochemical pattern. Once recovered from the operation, the patient's general condition improved remarkably, the oedema and ascites resolved completely on chronic haemodialysis therapy. However, high doses of oral lactulose were still needed to control the ammonia blood levels and to prevent hepatic coma.

A liver biopsy was repeated and showed a histological evolution of the incomplete septal cirrhosis to a picture of vanishing bile duct disease (grade IV). Immunohistochemical staining for hepatitis B and C were negative.

Because of the histological findings and the clinical situation, the patient was evaluated for a combined liver and kidney transplantation and subsequently accepted as a candidate despite the fact that he was only graded as a Child's class A.



   Discussion
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 Introduction
 Case
 Discussion
 References
 
The presence of a ‘full house’ positive immunostaining (C3, C1q, IgA, IgM, IgG) in a non-lupus type of membranoproliferative glomerulonephritis is rare in a patient with non-hepatitis related liver disease. There are various types of glomerulonephritis described in association with liver disease. Biopsies performed in patients with cirrhosis undergoing elective abdominal surgery, revealed a high incidence of glomerular involvement, sometimes as high as 90% [6]. Nowadays, most candidates awaiting orthotopic liver transplantation have an abnormal renal biopsy at the time of transplantation [7]. In these series of unselected liver disease, the type of renal involvement varies from minor glomerular abnormalities to hepatic glomerulosclerosis, membranoproliferative glomerulonephritis and IgA nephropathy. The most common and first described form of cirrhosis-associated glomerulonephritis is an IgA-type of nephropathy characterized by the presence of IgA2 [5,6]. When the relationship between hepatitis B and C infection and glomerulo nephritis became established, most of the other types of hepatic disease-related glomerulonephritis—such as membranoproliferative and membranous glomerulonephritis—were also better understood. As our patient had no evidence of either hepatitis B, C, or other types of infections, nor of SLE and cryoglobulinaemia, the occurrence of a membranoproliferative glomerulonephritis with ‘full house’ positive immunostaining remains remarkable.

The presence of a portosystemic shunt has also been reported to be associated with this type of glomerulonephritis [3,4]. Soma et al. [3] describes in his paper three patients who develop membranoproliferative glomerulonephritis 7–13 years after construction of a mesenterico-caval shunt for non-cirrhotic portal hypertension. None of the patients had evidence of cirrhosis at the moment of renal biopsy and in contrast with patients with idiopathic membranoproliferative glomerulonephritis, the immunostaining revealed not only IgA1 but also IgA2 in the cappillary loops. This made the author conclude that a portosystemic shunt per se can reduce the clearance of immune complexes formed in the portal circulation in such way that after a variable time period, an immune complex-mediated glomerulonephritis can develop. This seems to be confirmed by Karashima et al. [4], who found a congenital portosystemic shunt in two children presenting with membranoproliferative glomerulonephritis and nephrotic syndrome. A study by Dash et al. [2] comparing the incidence of glomerulonephritis in patients receiving a splenorenal shunt for portal hypertension due to non-cirrhotic portal fibrosis or extra-hepatic portal obstruction, supports this hypothesis only partially. An increased incidence of glomerulonephritis, predominantly IgA glomerulonephritis, was seen in those patients with non-cirrhotic portal fibrosis following portosystemic shunt but not in those with normal hepatic parenchymal architecture (extra-hepatic portal obstruction). A portosystemic shunt per se is not sufficient as a predisposing factor for glomerulonephritis, but can become so in the presence of a co-existing defective hepatic clearance of immune complexes. The shunt ratio [4] as well as the underlying hepatic disease [2] will ultimately determine the total net clearance of immune complexes. The fact that a very poor hepatic clearance of immune complexes without a shunt can lead to a membranoproliferative type of glomerulonephritis is also supported by Ori et al. [8]. They described a patient with cirrhosis due to veno-occlusive disease who developed a nephrotic syndrome due to membranoproliferative glomerulonephritis in the absence of a portosystemic shunt and without evidence for hepatitis B, C, cryoglobulinaemia, or SLE.

The presence of a portosystemic shunt in combination with a deteriorating hepatic function can probably explain our patient's evolution to developing a membranoproliferative type of glomerulonephritis and nephrotic syndrome. The ‘full house’ positive immunostaining as presented in the clinical setting of our patient is thought to be a unique finding (Table 2Go). Membranoproliferative glomerulonephritis with ‘full house’ positive immunostaining is commonly associated with lupus nephritis. Occasionally ‘full house’ immunostaining is seen, although not well understood, in patients with idiopathic ‘focal’ (mesangio) proliferative glomerulonephritis [9]. But in all published reports of membranoproliferative glomerulonephritis associated with non-hepatitis liver disease or portosystemic shunt, the immunostaining showed a classical pattern of C3, IgG and IgA with predominance of IgA2 [2,3,4,8].


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Table 2. Membranoproliferative glomerulonephritis associated with non-hepatitis liver disease

 
Both the de novo deposition of preformed circulating immune complexes and the in situ formation of immune complexes are thought to cause lupus nephritis. B-cell hyperactivity and/or T-suppressor cell deficiency in combination with a defective immune complex clearance is suspected to be responsible for the mechanism of renal immune complex formation in systemic lupus. Quantity, size and type of the immune complexes determine the microscopic appearance of lupus nephritis [10]. Genetic predisposition such as Fc-receptor deficiency and inherited deficiency of the erythrocyte C3b-receptor can further enhance impairment of the complement-dependent clearance of pathogenetic immune complexes in lupus nephritis [11]. Hence ‘full house’ positive membranoproliferative glomerulonephritis (lupus nephritis type IV World Health Organization Classification) can be considered as the expression of a more pronounced type of defective immune complex clearance by the kidney following abnormal immune complex overload or immune complex formation. The membranoproliferative type of glomerulonephritis with ‘full house’ immunostaining in our patient with liver disease and portosystemic shunt probably should be interpreted in the same way. Deterioration of the liver function in the presence of a functional portosystemic shunt was certainly a contributing factor to this state of impaired immune complex clearance. Although this is expected primarily to lead to an IgA2 overload and hence dominant IgA deposition, the full house immunostaining in our patient may show the importance of interindividual differences in immune complex formation and clearance by the kidney. Residual liver function and the degree of portosystemic shunting as well as genetically determined differences in immunity and immune complex clearance will determine the extent of renal involvement in patients with a portosystemic shunt.



   Notes
 
Correspondence and offprint requests to: Dirk Kuypers, MD, Department of Nephrology, Renal transplantation, University Hospitals Leuven, Herestraat 99, B-3000 Leuven, Belgium. Email: dirk.kuypers{at}uz.kuleuven.ac.be Back



   References
 Top
 Introduction
 Case
 Discussion
 References
 

  1. Oxford Textbook of Clinical Nephrology. University Press, Oxford: 1998; 591–603
  2. Dash SC, Bhuyan UN, Dinda AK et al. Increased incidence of glomerulonephritis following spleno-renal shunt surgery in non-cirrhotic portal fibrosis. Kidney Int1997; 52: 482–485[ISI][Medline]
  3. Soma J, Saito T, Sato H, Ootaka B, Abe K. Membranoproliferative glomerulonephritis induced by portosystemic shunt surgery for non-cirrhotic portal hypertension. Clin Nephrol1997; 48: 274–281[ISI][Medline]
  4. Karahima S, Hattori S, Nakazato H et al. Membranoproliferative glomerulonephritis in congenital portosystemic shunt without liver cirrhosis. Clin Nephrol2000; 53: 206–211[ISI][Medline]
  5. Lomax-Smith JD, Zabrowarny L, Howarth G, Seymour A, Woodroffe A. The immunochemical characterization of mesangial IgA deposits. Am J Pathol1983; 113: 359–364[Abstract]
  6. Callard P, Feldmann G, Prandi D et al. Immune complex type glomerulonefritis in cirrhosis of the liver. Am J Pathol1975; 80: 329–338[Abstract]
  7. Axelsen R, Crawford DH, Endre Z et al. Renal glomerular lesions in unselected patients with cirrhosis undergoing orthotopic liver transplantation. Pathology1995; 27: 237–246[ISI][Medline]
  8. Ori Y, Korzets A, Sandbank J, Lurie B, Zeidman A, Gafter U. Cirrhotic glomerulonefritis: an underdiagnosed condition. Isr J Med Sci1996; 32: 1222–1224[ISI][Medline]
  9. Jones E, Magil A. Nonsystemic mesangiopathic glomerulonefritis with ‘full house’ immunofluorescence. Am J Clin Path1982; 78: 29–34[ISI][Medline]
  10. Cameron J, Turner D, Ogg C et al. Systemic lupus with nefritis: a long-term study. Q J Med1979; 48: 1–24[Medline]
  11. Wilson JG, Wong W, Schur P, Fearon DT. Mode of inheritance of decreased C3b receptors on erythrocytes of patients with systemic lupus erythematosus. N Eng J Med1982; 307: 981–986[Abstract]
Received for publication: 8.11.00
Revision received 12. 6.01.



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