A PREGNANT FEMALE WITH FIBRILLARY GLOMERULONEPHRITIS AND LIVER CIRRHOSIS

Transcription

1 Case Report 201 A PREGNANT FEMALE WITH FIBRILLARY GLOMERULONEPHRITIS AND LIVER CIRRHOSIS Chi-Yuan Hung *, Chi-Jen Wu *, Han-Hsiang Chen *, Jui-Chi Yeh *, Tsang-En Wang **, Jeffrey Tzen ***, Yi-Chou Chen * Fibrillary glomerulonephritis is a morphologic diagnosis in which fibrillar aggregates resemble amyloid but are negative for Congo red stain. Extrarenal aggregates are reported but uncommon. We describe a 29-year-old female with nephrotic syndrome diagnosed at 22 weeks of pregnancy. After a premature delivery, she had a renal was interpreted as showing fibrillary glomerulonephritis. She had also had a partial hepatectomy to remove a 2 cm lesion in right hepatic lobe. The liver parenchyma had a particular pattern of cirrhosis. In addition, there were Congo-red-negative microfibrils in the fibrotic areas of the liver similar to those seen in the renal glomeruli. In both organs, the fibrils were about 13.5 to 16.5 nm in diameter and haphazardly arranged. The patient had hypocomplementemia, which is rare in previous reports of fibrillary glomerulopathy. Hypocomplementemia is known to be associated with poor clearance of immune complexes, but it is unclear whether this might have played a role in our patient s fibrillary glomerulopathy. (Acta Nephrologica 2006; 20: ) Key words: fibrillary glomerulonephritis; nephrotic syndrome; liver cirrhosis; hypocomplementemia INTRODUCTION Fibrillary glomerulonephritis (FGN) is a morphologic diagnosis in which immune aggregates in the glomeruli are organized into fibrils which resemble amyloid on hematoxylin and eosin or periodic acid Schiff staining but are Congo red- and thioflavin T-negative. Rosenmann and Eliakim first described this form of glomerulonephritis in Two morphological patterns have been described (Iskandar et al. 1992; 2 Alpers 1993, ; 4 Fogo et al ). A random arrangement of fibrils with a diameter of 15 to 30 nm is designated as fibrillary nephropathy. When fibrils are arranged in an ordered parallel array with 30 to 60 nm in diameter, the diagnosis is immunotactoid glomerulopathy (ITG). The difference of FGN and ITG is based on electron microscopic findings, the former show randomly deposited fibrils, whereas the latter presents parallel arranged bundles with microtubular substructure. 6 There is considerable overlap between these two forms. The mechanism of fibrillogenesis in immunoglobin deposits in general and particularly deposition in these two forms is unknown. 7 We report a patient with FGN who also had fibrillary deposits in the liver. The liver parenchyma had a particular of pattern cirrhosis and there were Congored-negative microfibrils in the fibrotic areas of the liver similar to those seen in the renal glomeruli. In both organs, the fibrils were about 13.5 to 16.5 nm in diameter and haphazardly arranged. The patient had hypocomplementemia, which is rare in previous reports of FGN. Hypocomplementemia is known to be associated with poor clearance of immune complexes, but it is unclear whether this might have played a role in our patient s fibrillary glomerulopathy. CASE A 29-year-old female had a past history of irregular menstrual period which had been treated with conjugated estrogen and medroxyprogesterone acetate for one year. She came to our hospital complaining of ankle edema and frothy urine for 6 weeks. She was found to be pregnant at 16 weeks of gestation. Blood pressure was 148/92 mmhg. She had no medical history of hypertension before. The ankle edema was attributed Division of Nephrology* and Gastroenterology**, Department of Internal Medicine; Division of Pathology***, Mackay Memorial Hospital, Taipei, Taiwan Received: December, 2005 Revised: March, 2006 Accepted: March, 2006 Address reprint request to: Dr. Yi-Chou Chen, No. 92, Section 2, Chung-Shan North Road, Taipei, Taiwan Tel: Fax: ext Keithhung@ms1.mmh.org.tw

2 202 C. Y. HUNG, C. J. WU, H. H. CHEN, et al. Vol. 20, No. 3, 2006 to pregnancy but worsened gradually during the recent weeks. Pre-eclampsia was not considered because there was an elevated blood pressure in the first 20 weeks of pregnancy. She returned 6 weeks later with a fever of 39 C and complaining of chills and worsening edema. Blood pressure was 201/112 mmhg. Laboratory data (Table 1) included a serum albumin of 1.6 gm/dl, total protein 2.9 gm/dl, serum cholesterol 296 mg/dl, triglycerides 76 mg/dl, and urinary protein 24.7 g/day. Serum and urine protein electrophoresis were evaluated and no monoclonal gammopathy was found. Serum glucose was 76 mg/dl, blood urea nitrogen 16 mg/dl, creatine 0.5 mg/dl, AST 42 u/l, ALT 25 u/l, and bilirubin was mildly elevated at 0.5/1.7 mg/dl (direct/total). Hemoglobin was 10.1 gm/dl and hematocrit 28.6%. In her urine sediment there were 5 RBC/HPF and 26 WBC/HPF. Bacteria were also present. No mention was made of casts. The immunologic findings (Table 1) included a negative anti-nuclear antibody (ANA) and anti-double stranded DNA. C3 (35 mg/dl), C4 (<10 mg/dl), and CH50 level (12.6 CH50/ml) were all low. There were no cryoglobulins. Markers for hepatitis B and C were negative. Her α-fetoprotein level (2.76 ng/dl) was low. She was admitted for evaluation of nephrotic syndrome. Unfortunately, she developed premature labor with contractions that were not amenable to tocolytics, and she delivered a live infant vaginally. Despite intensive care, the newborn did not survive. Because of mildly abnormal liver function tests, an abdominal echogram was performed which showed a hump-shaped lesion on the surface of the right lobe of the liver. In addition, very coarse echotexture of liver parenchyma was noted. A magnetic resonance imaging study confirmed the presence of the lesion (Fig. 1). Relatively smaller size of liver and prominence of its interlobar fissure is seen on axial T1 and T2 weighted image. Because of this finding and her renal abnormalities, a renal biopsy and partial hepatectomy to remove the liver mass were done. The kidney biopsy showed FGN, with subepithelial, intramembranous, subendothelial and mesangial deposits of randomly oriented 13.5 to 16.5 nm fibrils as shown by routine section and electron microscopy (Fig. 2). A Congo red stain of the fibrils was negative. On immunofluorescent staining, IgG was equivocal (±), IgA was 1+ positive, IgM 2+ positive, C3 1+ positive, C1q 1+ positive, kappa +1 positive, and lamda +3 positive. The hepatic tumor, to our surprise, was actually non-cirrhotic hepatic lobules with mild change in portal triads, situated in a background of cirrhotic liver tissue. The cirrhotic portion was characterized by a particular pattern of marked fibrosis involving, expanding, and Table 1. Clinical Data Serial Laboratory Data Time of Diagnosis 3 Months Later 6 Months Later Serum blood urea nitrogen (mg/dl) Serum creatinine (mg/dl) Urinary protein (g/24 hrs) Urine protein to creatinine ratio (mg/mg) Serum total protein (g/dl) Serum albumin (g/dl) Hemoglobin (g/dl) Hematocrit (%) Urinary sediment RBC 5 cells/hpf WBC 26 cells/hpf Bacteria (+) RBC 2 cells/hpf WBC 3 cells/hpf Granule cast / LPF: 0-2 Hyaline cast / LPF: 3-7 RBC 8 cells/hpf WBC 3 cells/hpf Bacteria (+) Serum C3 ( mg/dl) Serum C4 (17-37 mg/dl) <10 <10 Anti-dsDNA ANA Cryoglobulin Negative Negative Negative

3 Acta Nephrologica A Pregnant female with Fibrillary GN and Liver Cirrhosis Fig. 1. MRI : A bulging mass lesion is noted over right lobe of liver (arrow). 203 extending along the portal tree, but lacking the bridging features seen in chronic viral hepatitis or alcoholic cirrhosis, or biliary cirrhosis. The fibrotic pattern led to a blunt end or round islands of fibrotic portal areas occasionally (Fig. 3-a). Concentrical fibrosis around bile ducts and blood vessels was noted. Proliferation of biliary ductules was present, and there was bile stasis noted in some bile canaliculi mainly along the limiting plate (Fig. 3-b). Lymphocytic infiltration was mild and scattered, and there was neither periductal arrangement nor piece-meal necrosis. The portal triads within the hepatic lesion showed only minimal fibrotic change and mild bile ductular proliferation. The hepatocytes within and outside the lesion were basically unremarkable except for increase of lipofudin. On electron microscopy at low magnification ( 2000), over the fibrotic portal triads of the liver, aggregates of microfibrils were identified between collagen fibers around bile ductules and vessels. At a higher power ( 20,000), the microfibrils appeared to be haphazardly oriented and measured 13.5 nm in diameter (Fig. 4). A Congo red stain of the microfibrils was negative. It thus appeared that the patient had fibrillary deposits on both her kidney and liver. In addition to antibiotics for a presumed urinary tract infection, she was treated with diuretics and albumin and plasma transfusions. However, severe edema persisted and she was therefore given steroid pulse therapy twice, followed by maintenance oral methylprednisolone. Her proteinuria improved falling from 24.7 gm daily on admission to 2.46 gm daily 3 months later (Table 1). DISCUSSION Fig. 2. Renal biopsy : Electron Microscopy. There are deposits of fibrils, measuring nm in diameter, in subepithelial, intramembranous, subendothelial and mesangial areas. At high power ( 20,000) FGN is a rare disease with an incidence of around 1% in a kidney biopsy series. It should be differentiated from amyloidosis, diabetes mellitus, cryoglobulinemia, systemic lupus erythematosus, and various paraproteinemias.8,12,14 This may be a new form of primary glomerular disease. In patients with FGN, extrarenal fibrillary deposits have been reported previously in the lung,9 liver,10,12 and bone marrow.11,12 Our patient s renal biopsy was completely consistent with the diagnosis of FGN.5,6,13,14 The immunofluorescence microscopy showed variable degree of mesangial and capillary wall staining for IgG, IgA, IgM, C3, and C1q. Both kappa and lambda light chains were positive staining and the polyclonal immunoglobin deposits were compatible with previous reports.6,14 The microfibrils in the liver were very similar to those in the kidney in terms of size and arrangement. It is difficult to interpret because of the resemblance of the

4 204 C. Y. HUNG, C. J. WU, H. H. CHEN, et al. Vol. 20, No. 3, 2006 a. H-E stain (x40) b. H-E stain (x100) c. Masson's trichome stain (x40) Fig. 3. Liver, partial hepatectomy: Light microscopy. Microscopically, the section shows cirrhosis of liver parenchyma characterized by fibrous septa (positive for Masson's trichome [Fig. 3-c] and silver stain, negative for PAS stain) connecting portal tracts. The fibrotic pattern led to an blunt end or round islands of fibrotic portal areas (Fig. 3-a). Proliferation of biliary ductules was present, and there was bile stasis noted in some bile canaliculi mainly along the limiting plate (Fig. 3-b). fibrillary structure of the liver to the deposits of FGN. We believe the fibrils in both sites were thus part of the same process, though it was impossible to tell which site was involved first. Both her nephrotic syndrome and cirrhosis were discovered at the same time, during her pregnancy. We rule out the possibility of pre-eclampsia because there was an elevated blood pressure in the first 20 weeks of pregnancy. She had no obvious risk factors for cirrhosis, for example, viral hepatitis or alcohol abuse. She had no history of other autoimmune disease and her antinuclear antibody was negative, so the diagnosis of autoimmune hepatitis was not considered very likely. Estrogen and progesterone have been implicated in biliary tract disease, but no evidence of cirrhotic potential of these two drugs. Therefore, it is quite possible that her cirrhosis was part of the same disease process as her fibrillary glomerulonephritis. In most reported cases of FGN, serum complement levels have been normal. Hypocomplementaemia is a rare serologic finding in FGN.14 However, three patients have previously been described who had FGN associated with hypocomplementaemia, especially decreases in C Factor H complement deficiency presenting with FGN also may cause hypocomplementaemia.18 The mechanism of glomerular immune injury is variable, but complement has been demonstrated to play an important role.19 Complement activation induces cytokine release and other intracellular signaling mechanisms. In addition, it is associated with recruitment of neutrophils and platelets, formation of the membrane attack complex,

5 Acta Nephrologica A Pregnant female with Fibrillary GN and Liver Cirrhosis 205 Fig. 4. Liver, partial hepatectomy: Electron Microscopy. At low magnification ( 2000), aggregates of microfibrils are identified between collagen fibers around bile ductules and vessels. At higher power ( 20,000), the microfibrils appear to be hapazardly oriented and measure 13.5 nm in diameter (yellow square). and clearance of immune complexes. 15 Hypocomplementemia associated with immune complex diseases, such as nephritis and systemic lupus erythematosus.16 Our patient s low complement levels may have contributed to the delayed clearance of immune complexes, allowing for fibril deposition. The association between liver disease and hypocomplementemia has been discussed previously. Hypo- complementemia is commonly observed in patients with alcoholic cirrhosis.20 Up to 30% of patients with chronic hepatitis C have hypocomplementemia and frequently have extrahepatic manifestations.21 A close association of hypocomplementemia with HCV viremia among apparently healthy blood donors was reported previously.22 Again, our patient had no evidence of viral or alcoholic liver disease, so it is not clear if there was any relation-

6 206 C. Y. HUNG, C. J. WU, H. H. CHEN, et al. Vol. 20, No. 3, 2006 ship between her hypocomplementemia and the liver disease. In patients with FGN, therapeutic trials with steroids alone, steroids with immunosuppressants, and steroids with plasmapheresis have yielded a response in less than 10% of cases in terms of clinical remission of proteinuria. 8 Two reports did suggest the possibility of remission in some patients, especially if treated early. 23,24 Fortunately, our patient had a partial remission with marked decrease of her proteinuria after pulse and maintenance steroid therapy. Cyclophosphamide has been tried in patients with rapidly progressive renal failure. 25 We chose not to use cyclophosphamide in our patient because of fear of pancytopenia and low response rate to cytotoxic therapy in previous reports. 7 Renal transplantation is another consideration for fibrillary glomerulonephritis, but about 50% of patients have a recurrence. 26 In conclusion, fibrillary glomerulonephritis with hypocomplementemia is rare. Progression to ESRD appears to occur in approximately 50% of FGN patients. Hypocomplementemia is known to be associated with poor clearance of immune complexes, but it is unclear whether this might have played a role in our patient s fibrillary glomerulopathy. REFERENCES 1. Rosenmann E, Eliakim M: Nephrotic syndrome associated with amyloid-like glomerular deposits. Nephron 1977; 18: Iskandar SS, Falk RJ, Jennette, JC: Clinical and pathologic features of fibrillary glomerulonephritis. Kidney Int 1992; 42: Alpers, C.E. Fibrillary glomerulonephritis andimmunotactoid glomerulopathy: Two entities, not one. Am J Kidney Dis 1993; 22: Alpers CE: Glomerulopathies of dysproteinemias, abnormal immunoglobulin deposition, and lymphoproliferative disorders. Curr Opin Nephrol Hypertens,1994; 3: Fogo A, Qureshi N, Horn RG: Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy. Am J Kidney Dis 1993; 22(3): Iskandar SS, Herrera GA: Glomerulopathies with organized deposits. Seminars in Diagnostic Pathology 2002; 19: Melvin M, Schwartz, Stephen M. Korbet, Edmund J. Lewis: Immunotactoid glomerulopathy. J Am Soc Nephrol 2002; 13: Korbet SM, Schwartz MM, Lewis EJ: The fibrillary glomerulopathies. Am J Kidney Dis 1994; 23: Masson RG, Rennke HG, Gottlieb MN: Pulmonary hemorrhage in a patient with fibrillary glomerulonephritis. N Engl J Med 1992; 326: Ozawa K, Yamabe H, Fukushi K, et al: Case report of amyloidosis-like glomerulopathy with hepatic involvement. Nephron 1991; 58(3): Wallner M, Prischl FC, Hobling W, et al: Immunotactoid glomerulopathy with extrarenal deposits in the bone, and chronic cholestatic liver disease. Nephrol Dial Transplant 1996; 11: Hvala A, Ferluga D, Vizjak A, Kolselj-Kajtna M: Fibrillary noncongophilic renal and extrarenal deposits: a report on 10 cases. Ultrastruct Pathol 2003; 27: Bridoux F, Hugue V, Coldefy O, et al: Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features. Kidney International 2002; 62(5): Jordan L, Rosenstock, Glen S. Markowitz, et al: D Agati Fibrillary and immunotactoid glomerulonephritis: Distinct entities with different clinical and pathologic features Kidney International 2003; 63(4): Deborah Bachtold Adey, Bruce R, MacPherson, Gerald Groggel: Glomerulonephritis with associated hypocomplementemia and crescents: an unusual case of fibrillary glomerulonephritis. J Am Soc Nephrol 1995; 6: Schifferli JA, Merot Y, Cruchaud A, Chatelanat F: Immunotactoid glomerulopathy with leucocytoclastic skin vasculitis and hypocomplementemia: a case report. Clin Nephrol 1987; 27: Suzuki S, Konta T, Koizumi R, et al: Fibrillary glomerulonephritis with hypocomplementemia. Internal Medicine; Vol 42, Issue 8, 1 August 2003, Zelal B, Demet T, Isin K, et al: Factor H deficiency and fibrillary glomerulopathy. Nephrol Dial Transplant 2004; 19: Couser WG: Mediation of immune glomerular injury. J Am Soc Nephrol 1990; 1: Sopena B, Martinez-Vazquez C, de la Fuente J, et al: Serum levels of immunoglobulins and complement in alcoholic liver disease. Revista Clinica Espanola. 1993; 193(8): Ignatova TM, Aprosina ZG, Serov VV, et al: Extrahepatic manifestations of chronic hepatitis C. Terapevticheskii Arkhiv 1998; 70(11): Itoh K, Tanaka H, Shiga J, et al: Hypocomplementemia associated with hepatitis C viremia in sera from voluntary blood donors. American Journal of Gastroenterology 1994; 89(11): Dickenmann M, Schaub S, Nickeleit V, et al: early diagnosis associated with steroid responsiveness. Am J Kidney Dis 2002; 40(3): E Clarles E, Alpers CE: Fibrillary glomerulonephritis and immunotactoid glomerulopathy: Two entities, not one. Am J Kidney Dis 1993; 22: Blume C, Ivens K, May P, et al: Fibrillary glomerulonephritis associated with crescents as a therapeutic challenge. Am J Kidney Dis 2002; 40(2): Pronovost PH, Brady HR, Gunning ME, Espinoza O, Rennke HG: Clinical features, predictors of disease progression and results of renal transplantation in fibrillary/immunotactoid glomerulopathy. Nephrol Dial Transplantation 1996; 11: