Home About us Current issue Ahead of Print Back issues Submission Instructions Advertise Contact Login   

Search Article 
Advanced search 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 1881 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 

ARTICLE Table of Contents   
Year : 2000  |  Volume : 11  |  Issue : 3  |  Page : 414-420
Glomerulopathy with Liver Disease: Patterns and Management

Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India

Click here for correspondence address and email

How to cite this article:
Dash SC, Bhowmik D. Glomerulopathy with Liver Disease: Patterns and Management. Saudi J Kidney Dis Transpl 2000;11:414-20

How to cite this URL:
Dash SC, Bhowmik D. Glomerulopathy with Liver Disease: Patterns and Management. Saudi J Kidney Dis Transpl [serial online] 2000 [cited 2021 Apr 10];11:414-20. Available from: https://www.sjkdt.org/text.asp?2000/11/3/414/36663
The first reports of glomerulopathy in patients with cirrhosis of liver were published nearly five decades ago. [1],[2] Glomerular changes occur primarily in patients with cirrhosis of the liver and acute or chronic viral hepatitis. In recent years, glomerulopathy in patients of non-cirrhotic portal fibrosis who had undergone splenorenal shunt surgery has been reported. 3 This review will briefly discuss each of these conditions.

A. Glomerulopathy Associated with Liver Cirrhosis

Bloodworth and Sommers described thickening of the glomerular mesangial stalk and capillary wall, which they termed cirrhotic glomerulosclerosis. [4] With the use of electron microscopy it was revealed that mesangial stalk thickening was due to both an increase in mesangial matrix and amorphous deposits with clear halos. [5] IgA was demonstrated as the main immuno­globulin deposited in the glomerular mesangium. Callard et al [6] also demons­trated mesangial and subendothelial deposits of IgA along with mesangial thickening in the large majority of renal biopsies taken during portocaval anastomosis.

Glomerulonephritis due to liver cirrhosis is generally clinically silent and is characterized by mild microhematuria and proteinuria. Glomerular lesions showing mesangial IgA deposits in addition to small amounts of other immunoglobulins and complements are most commonly seen in patients of alcoholic cirrhosis, but it may also occur in viral and cryptogenic chronic hepatitis, and in chronic schistosomiasis with portal hypertension. [7] Glomerulo­pathies in patients of cirrhosis of liver occur in 50-100 percent of cases. [8],[9]

In a series of 100 patients of cirrhosis, Berger J, et al [10] observed mesangial IgA deposition with subendothelial extension in 61 patients. In four patients, linear IgA and/or IgG deposition was noted along the glomerular basement membrane whereas in three there were scanty deposits of IgG only. No immunoglobulin was demonstrated on immunofluorescence in the remaining 32 patients. On light microscopy two patients had membranoproliferative (MPGN), one had endo- and extra-capillary glomerulo­nephritis. Three patients showed focal glomerular changes despite diffuse mesangial IgA deposits. Mesangial stalk thickening without IgA deposits was seen in the remaining patients. As expected, patients with MPGN manifested with heavy proteinuria while patients of endo- and extra-capillary proliferation presented with gross hematuria in addition to proteinuria. A significant number of patients had renal insufficiency. The authors, however, admitted to less accurate assessment for proteinuria and hematuria in these patients.

Thus, it is clear that in cirrhosis of the liver glomerular changes are quite common. There are two main recognized patterns (a) glomerulopathy without proliferation and (b) glomerulonephritis with proliferation. In the former, electron microscopy reveals electron dense deposits that are mainly mesangial but frequently extend into the subendothelial space. IgA is the main immunoglobulin in glomerular deposits, although IgG and/or IgM may co-exist. These deposits are associated with widening of the mesangial matrix.

In the proliferative group, glomerular changes are characterized by a slight mesangial, endo- and extracapillary prolife­ration and mesangial interposition similar to MPGN.IgA is the dominant immuno­globulin in the deposits.

Clinical Features

Patients with endocapillary proliferation present clinically with features of acute glomerulonephritis, whereas those with membranoproliferative changes have either proteinuria or microscopic hematuria or have no urinary abnormalities. In liver cirrhosis glomerulonephritis is a silent disease and therefore, routine urine examination for proteinuria and hematuria should always be done in search of possible glomerulopathy. Gross hematuria may rarely occur. These patients generally do not progress to chronic renal failure. However, patients with MPGN or endomesangial proliferation can present with nephrotic range proteinuria. Detection of hypertension in patients with cirrhosis of the liver should raise suspicion of unrelated underlying glomerular disease because hypertension is highly unlikely in cirrhosis. Circulating immune complexes and antibodies against dietary and bacterial antigens have also been found in patients with liver cirrhosis. Immune complexes are mainly IgA (IgA1 and IgA2 subclasses). Similarly mixed cryoglobulins containing IgA have also been found in such patients, although no correlation between these antibodies and glomerulonephritis has been established.


It is not clearly understood how glome­rulopathy occurs in patients with liver cirrhosis. Some cases of glomerulonephritis could be related to hepatitis C or hepatitis B antigens. Cryoglobulinemia complicating hepatitis C infection may induce immune complex glomerulonephritis. However, these antigens are neither frequently found in liver cirrhosis nor is cryoglobulinemia commonly seen in hepatitis-C positive patients. It is interesting to note that glomerulonephritis has also been described in alcoholic hepatitis and in viral hepatitis without cirrhosis.

It is probable that IgA produced by intestinal plasma cells interacts with food antigens that cross-intestinal mucosa damaged by alcohol, to induce formation of immune complexes. Experimentally, immune dysfunction has been induced in the mucosal immune system by infusion of liquid diet containing alcohol, which led to IgA nephropathy. [11] Furthermore, duration of alcohol ingestion has been linked to incidence of glomerulonephritis.

Serum levels of IgA were high in 77 to 91 percent of patients. [12],[13] The high level is due to increased synthesis of antibodies to bacterial and dietary antigens. Cirrhotic patients with portocaval shunts are the ones who demonstrate higher levels of IgA because of impaired liver catabolism of polymeric IgA and immune complexes. [12],[13]

Enhanced synthesis of IgA by peripheral lymphocytes has also been reported, in addition to decreased catabolism, as the cause of high IgA levels in alcoholic cirrhosis. [11] Complement C3 levels may be low in these patients. No correlation has been observed between hypocomplemen­temia and the degree of liver dysfunction.


Glomerular changes in cirrhosis of the liver are usually related to the liver dysfunction, although de novo glomerulonephritis may occur. Treatment therefore is symptomatic. Adequate control of blood pressure by angiotensin converting enzyme (ACE)­inhibitors is advised if the glomerular filtration rate (GFR) is above 40 ml/min. If proteinuria is below 1 g/24 hours, patients should be just observed with symptomatic treatment. When proteinuria is between 1-3 g/24 hours and GFR is normal, again no specific treatment is advised. If there is associated renal insufficiency fish oil may be useful, although controlled studies on the effects of fish oil therapy in IgA nephropathy secondary to liver disease are lacking. If proteinuria exceeds 3 g/24 hours and the GFR is above 70 ml per minute a course of prednisolone may be tried.

In non-cirrhotic portal fibrosis (NCPF), increased incidence of glomerulonephritis has been described particularly following splenorenal shunt surgery. [3] NCPF forms nearly 20-30% of all patients with portal hypertension in India undergoing surgery or sclerotherapy. Only about seven percent of these patients show mild proteinuria. However, 32% of the patients developed nephrotic syndrome after splenorenal shunt surgery in five years. Renal histology in these cases showed MPGN (8.5%), mesangial proliferative glomerulonephritis (9%), no change (3%) and sclerosing glomerulo­nephritis (1.5%). Immunofluorescence revealed glomerular IgA 2 deposition in all cases indicating IgA was derived from gastrointestinal tract. It is likely that the shunting procedure done to decongest splanchnic bed in NCPF enhances direct portosystemic circulation, which increases entry of bacterial and food antigens bypassing the hepatic Kupffer cells. Consequently IgA serum levels become elevated in these patients.

B. Glomerulopathy Associated with Acute Viral Hepatitis and Hepatitis B Infection.

Renal function is mildly impaired in most cases of acute viral hepatitis. Modest proteinuria, hematuria and mild reduction in GFR are usual features. Renal histology is marked by mild degree of mesangial proliferative glomerulonephritis. Mesangial deposits of IgG, IgM and complements are detected on immunofluorescence. The proteinuria disappears and the GFR returns to normal with recovery from acute viral hepatitis. However, more severe impairment of renal function has been reported in patients with persistent hepatitis B antigenemia (HBsAg) associated with chronic active hepatitis. Such renal involvement has also been described in patients who are infected with hepatitis B-virus without co-existent chronic hepatitis. The role of hepatitis in the pathogenesis of glomerulonephritis is unclear. It is speculated that reduced detoxification of immune complexes during liver cell impairment leads to the tissue deposition and damage of glomeruli. Three major forms of renal disease have been described: membranous nephropathy, membranopro­liferative glomerulonephritis, and poly­arteritis nodosa. [14],[15],[16]

(a) Membranous Nephropathy (MGN):

Hepatitis B virus can induce subepithelial immune deposits containing HBeAg and anti-Hbe antibody responsible for MGN leading to l proteinuria and the nephritic syndrome. [17],[18] This condition is more common in children and, in many cases, resolves spontaneously. Serologically, these children usually show anti-Hbe antibodies in the circulation. Resolution is uncommon in adults and most of them develop progressive disease. [18]

(b) Membranoproliferative Glomerulo­nephritis (MPGN):

MPGN associated with HBV is an immune complex disease characterized by depo­sition of circulating antigen antibody complex in the mesangium and sub­endothelial space. Both HBsAg and HBeAg deposition have been demonstrated. [17] Clinically the disease manifests with proteinuria and microscopic hematuria with a progressive course and deterioration of renal function over few months to few years similar to idiopathic MPGN.

c) Polyarteritis Nodosa (PAN):

Large vessel vasculitis, like PAN, can be induced by HBV in which circulating antigen-antibody complexes are deposited in the subendothelium. [14],[15] This disease is often idiopathic, although HBV association has been reported in 10 percent of the cases. Moreover, PAN was reported in HBV infected patients who have very mild or absent hepatitis. Vasculitis in a typical case occurs after four months of infection. Finding of HBsAg and HBeAg in blood, and viral replication documented by seropositivity of HBV DNA suggests that the disease may be related to HBV. Anti neutrophil cytoplasmic antibody (ANCA) is negative in these patients.


Immunosuppressive therapy with cortico­steroids or cytotoxic drugs in HBV induced renal disease is not beneficial and is contraindicated in the presence of chronic hepatitis. In children recovering from liver disease, spontaneous recovery of memb­ranous nephropathy can occur. Therefore, the course of the liver disease and the severity of the renal involvement largely determine prognosis. Antiviral therapy with interferon alpha has been found beneficial in patients with persistent nephrotic syndrome.

Interferon alpha has been found more effective in children and in patients from non-endemic areas, [19],[20],[21] whereas it is not so beneficial in adults and those from endemic areas. A study from the national institute of health (NIH) evaluated 15 adults (11 with MGN and 4 with MPGN) who were treated with five million units subcutaneously for six weeks. [22] Eight patients responded with seroconversion, i.e. became negative for HBeAg and HBV DNA, and their proteinuria disappeared. Seven non­responders had higher baseline values of HBeAg and HBV DNA titer. A combination of interferon alpha with famciclovir has shown better response and rapid decline in HBV DNA, which was accompanied by clinical improvement and seroconversion within one-year. [21] Adenosine arabinoside, in combination with thymic extract has been used in order to treat this viral infection and enhance the immune system. In one series, 24 patients who had MGN showed remission with this mode of therapy. [23]

C. Hepatitis C Virus (HCV) Related Nephropathies

Although association between Hepatitis C virus and certain renal diseases is well established, the role of HCV induced hepatitis in the development of glomerulopathy is still speculative. Three major types of renal disease have been recognized (i) Mixed Cryoglobulinemia (ii) Membranoproliferative glomerulonephritis (iii) Membranous glomerulopathy. [24],[25],[26],[27],[28]

Mixed cryoglobulinemia is characterized by features of systemic vasculitis, fever, arthralgia, palpable purpura, hypocomple­mentemia and renal disease. Hematuria, proteinuria and variable degrees of renal insufficiency have been observed. Renal biopsy usually reveals a picture of MPGN along with intraluminal thrombi on light microscopy and 'fingerprint' appearance representing dense deposits on electron microscopy. Recently, 95 percent of patients with type II or essential mixed cryoglobulinemia have shown circulating anti HCV antibodies. Polyclonal IgG anti HCV antibodies and HCV RNA have been detected within the cryoprecipitate and also in the plasma. [25],[26]

MPGN is well known to be associated with HCV infection. Cryoglobulinemia is present in about 40 percent of the cases.

However, in our own data of 53 MPGN patients, although seven (13%) were HCV positive, none had cryoglobulinemia. [29] Similarly HCV associated type I MPGN is uncommon in France. [30] In the USA, it was shown in two out of 17 cases, [31] while in Japan the incidence is as high as 60 percent. [32] Most of these patients show elevated transa­minases suggestive of ongoing chronic hepatitis. HCV antigen and antibody could be demonstrated in the cryoprecipitates of those who had cryoglobulinemia.

HCV associated membranous nephropathy has been reported. HCV RNA was demonstrated in the kidney in patients with hepatitis and nephrotic syndrome. Complement levels tend to be normal; rheumatoid factor and cryoglobulins are absent in the HCV associated MGN.


Establishing the diagnosis of HCV infection by serology, as well as by immuno­histochemical localization of the virus in the kidney, is very important before treatment is attempted, [24],[28] because immuno­suppressants, sometimes prescribed in idiopathic disease, will be contraindicated when the nephropathy is associated with viral disease. Anti viral therapy with interferon alpha in patients with HCV­related renal disease is beneficial in, at least, 50 percent of the cases. Patients who respond should receive interferon alpha for at least 12 months. Higher dose (10 million units daily for 2 weeks) of interferon alpha has been found to be more effective if lower dose therapy fails. However, interferon therapy should be delayed for two to four months in patients with severe acute disease (manifesting with renal failure and severe neurologic involvement). Such patients should be better treated first by plasmapheresis and immunosuppressive therapy.

   References Top

1.Baxter JH, Ashworth CT. Renal lesion in portal cirrhosis. Arch Pathol 1946;41:476-9.  Back to cited text no. 1    
2.Patek AJ, Seegal D, Bevana M. The association of cirrhosis of liver and glomerulonephritis. Report of 14 cases. Am J Med Sci 1981;991:77-80.  Back to cited text no. 2    
3.Dash SC, Bhuyan UN, Dinda AK, et al. Increased incidence of glomerulonephritis following splenorenal shunt surgery in non­cirrhotic portal fibrosis. Kidney Int 1997;52:482-5.  Back to cited text no. 3  [PUBMED]  
4.Bloodworth JM Jr, Sommers SC. Cirrhotic glomerulosclerosis: a renal lesion associated with hepatic cirrhosis. Lab Invest 1959;8: 962-5.  Back to cited text no. 4  [PUBMED]  
5.Sakaguchi H, Dachs S, Grisman E, Paronetto F, Salomon M, Churg J. Hepatic glomerulosclerosis. An electron micros­copic study of renal biopsies in liver diseases. Lab Invest 1965;14:533-41.  Back to cited text no. 5    
6.Callard P, Feldman G, Prandi D, et al. Immune complex type glomerulonephritis in cirrhosis of liver. Am J Pathol 1975;80: 329-­40.  Back to cited text no. 6    
7.Nakamoto Y, Iida H, Kobayashi K, et al. Hepatic glomerulonephritis. Characteristics of hepatic IgA glomerulonephritis as the major part. Virchows Arch Pathol Anat 1981;392:45-54.  Back to cited text no. 7    
8.Jones WT, Rao DR, Braunstein H. The renal glomerulus in cirrhosis of liver. Am J Pathol 1961;39:393-404.  Back to cited text no. 8    
9.Noel LH, Droz D, Gascon M, Berger J. Priamry IgA nephropathy: from the first described cases to the present. Semin Nephrol 1987;7:351-4.  Back to cited text no. 9  [PUBMED]  
10.Berger J, Yaneva H, Nabarra B. Glomerular changes in patients with cirrhosis of liver. Adv Nephrol 1978;3-14.  Back to cited text no. 10    
11.Coppo R, Arico S, Piccoi G, et al. Presence and origin of IgA1 and IgA2 containing circulating immune-complexes in chronic alcoholic liver disease with or without glomerulonephritis. Clin Immunol Immunopathol 1985;35:1-8.  Back to cited text no. 11    
12.Woodroffe AJ, Gormly AA, McKenjee PE, et al. Immunologic studies in IgA nephropathy. Kidney Int 1980;18:366-74.  Back to cited text no. 12    
13.Sancho J, Egido J, Sanchez-Crespo M, Blasco R. Detection of monomeric and polymeric IgA containing immune complexes in serum and kidney from patients with alcoholic liver disease. Clin Exp Immunol 1981;47:327-35.  Back to cited text no. 13    
14.Johnson RJ, Couser WG. Hepatitis B infection and renal disease: clinical, immunopathogenetic and therapeutic considerations. Kidney Int 1990;37:663-76.  Back to cited text no. 14  [PUBMED]  
15.Lai KN, Lai FM. Clinical features and natural course of hepatitis B virus-related glomerulopathy in adults. Kidney Int Suppl 1991;35:S40-5.  Back to cited text no. 15  [PUBMED]  
16.Levy M, Chen N. Worldwide perspective of hepatitis B-associated glomerulo-nephritis in the 80s. Kidney Int Suppl 1991;35:S24-33.  Back to cited text no. 16  [PUBMED]  
17.Takekoshi Y, Tochimaru H, Nagata Y, Itami N. Immunopathogenetic mechanisms of hepatitis B virus-related glomerulo-pathy. Kidney Int Suppl 1991;35:S34-9.  Back to cited text no. 17  [PUBMED]  
18.Lai KN, Li PK, Lui SF, et al. Membranous nephropathy related to hepatitis B virus in adults. N Engl J Med 1991;324:1457-63.  Back to cited text no. 18  [PUBMED]  
19.Lisker-Melman M, Webb D, Di Bisceglie AM, et al. Glomerulonephritis caused by chronic hepatitis B virus infection: treatment with recombinant human alpha-interferon. Ann Intern Med 1989;111:479-83.  Back to cited text no. 19  [PUBMED]  
20.Lin CY. Treatment of hepatitis B virus­associated membranous nephropathy with recombinant alpha-interferon. Kidney Int 1995;47:225-30.  Back to cited text no. 20  [PUBMED]  
21.Kruger M, Boker KH, Zeidler H, Manns MP. Treatment of hepatitis B-related poly­arteritis nodosa with famciclovir and interferon alfa-2b. J Hepatol 1997;26:935-9.  Back to cited text no. 21    
22.Conjeevaram HS, Hoofnagle JH, Austin HA, et al. Long-term outcome of hepatitis B virus­related glomerulonephritis after therapy with interferon alpha. Gastroenterology 1995;109:540-6.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.Lin CY, Lo S. Treatment of hepatitis B virus-associated membranous nephropathy with adenine arabinoside and thymic extract. Kidney Int 1991;39:301-6.  Back to cited text no. 23    
24.Johnson RJ, Willson R, Yamabe H, et al. Renal manifestations of hepatitis C virus infection. Kidney Int 1994;46:1255-63.  Back to cited text no. 24  [PUBMED]  
25.Misiani R, Bellavita P, Fenili D, et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 1992;117:573-7.  Back to cited text no. 25  [PUBMED]  
26.Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992; 327:1490-5.  Back to cited text no. 26  [PUBMED]  
27.Sansonno D, Gesualdo L, Manno C, Schena FP, Dammacco F. Hepatitis C virus-related proteins in kidney tissue from hepatitis C virus-infected patients with cryoglobulinemic membranoproliferative glomerulonephritis. Hepatology 1997;25: 1237-44.  Back to cited text no. 27  [PUBMED]  [FULLTEXT]
28.Johnson RJ, Gretch DR, Yamabe H, et al. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 1993;328:465-70.  Back to cited text no. 28  [PUBMED]  [FULLTEXT]
29.Prakash S, Dash SC, Kumar A, Dinda AK, Panda SK. Is hepatitis C virus important causative agent of membranoproliferative glomerulonephritis (abstract). Indian J Nephrol 1996;6:93.  Back to cited text no. 29    
30.Rostoker G, Desforges L, Ben Maadi A, et al. Low prevalence of antibodies to hepatitis C virus among adult patients with idiopathic membranoproliferative type I glomerulonephritis in France (letter). Nephron 1995;69:97.  Back to cited text no. 30    
31.Cosio FG, Roche Z, Agarwal A, et al. Prevalence of hepatitis C in patients with idiopathic glomerulopathies in native and transplant kidneys. Am J Kidney Dis 1996;28:752-8.  Back to cited text no. 31  [PUBMED]  
32.Yamabe H, Johnson RJ, Gretch DR, et al. Hepatitis C virus infection and membrano­proliferative glomerulonephritis in Japan. J Am Soc Nephrol 1995;6:220-3.  Back to cited text no. 32  [PUBMED]  

Correspondence Address:
Suresh C Dash
Department of Nephrology, All India Institute of Medical Sciences, New Delhi - 110029
Login to access the Email id

PMID: 18209333

Rights and Permissions


    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
    Email Alert *
    Add to My List *
* Registration required (free)  


 Article Access Statistics
    PDF Downloaded940    
    Comments [Add]    

Recommend this journal