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Quiz Page April 2007
QUIZ PAGE APRIL 2007 CLINICAL PRESENTATION A 60-year-old African-American man with hepatitis C virus (HCV) infection presented with anemia, swelling of extremities, and acute renal failure. Liver biopsy 1 year earlier showed chronic hepatitis and early bridging fibrosis. He was treated with interferon (IFN) alfa and ribavirin. He has no family history of kidney disease, and prior laboratory urine test results and creatinine levels were normal. Test results for human immunodeficiency virus were negative. He now has a spot urine proteincreatinine ratio of 16, hematuria, and increased serum creatinine level of 2.3 mg/dL (175 mol/L). A renal biopsy was performed.
Figure 1. Light microscopy (periodic acid–Schiff [PAS]; origi-
nal magnification ⫻400).
f What is your clinical differential diagnosis? f What do you see by light and electron microscopy? Figure 2.
⫻6,000).
American Journal of Kidney Diseases, Vol 49, No 4 (April), 2007: p xlix-li
Electron microscopy (original magnification
xlix
QUIZ PAGE APRIL 2007 ANSWERS DISCUSSION f What is your clinical differential diagnosis? With a history of HCV liver disease, HCV glomerulonephritis should be ruled out. Classically, glomerular disease in patients with HCV is likely to be membranoproliferative glomerulonephritis (MPGN) with cryoglobulinemia, but other glomerular diseases, such as membranous glomerulopathy, MPGN without cryoglobulinemia, diffuse proliferative and exudative glomerulonephritis, crescentic glomerulonephritis, immunoglobin A nephropathy, mesangial proliferative glomerulonephritis, and, rarely, fibrillary glomerulonephritis, are possible. f What do you see by light and electron microscopy? As seen in Fig 1, the glomerulus is remarkable for prominent podocytes covering almost the entire outer part of the capillaries. Below the proliferating podocytes, the capillary lumina are closed and the wall of the capillaries appears collapsed. There is no glomerular basement membrane duplication to suggest MPGN or mesangial cell proliferation to suggest immunoglobin A or mesangial proliferative glomerulonephritis. There are no crescents. The biopsy specimen also shows chronic inflammatory cells in the interstitium and tubular atrophy, with l
tortuous dilatation of some tubules highlighted by the PAS stain. Tubular lumens are dilated and contain PAS-positive cast material. Immunofluorescence microscopy shows sparse nonspecific deposits, but no evidence of such immune complex– mediated glomerular disease as membranous glomerulopathy. Collapsing focal segmental glomerulosclerosis (FSGS) is characterized by implosive collapse of the tuft, wrinkling and retraction of the glomerular basement membrane, podocyte hypertrophy and hyperplasia, and tubular degenerative changes. Microcystic dilatation of tubules with large and tortuous PAS-positive casts (that often have a crackledpaper appearance) are characteristic of human immunodeficiency virus–associated collapsing glomerulopathy. The electron micrograph (Fig 2) shows a partially collapsed capillary loop. Foot processes are effaced (arrow). The cytoplasm of the corresponding podocyte contains numerous cytoplasmic organelles. Typically, electron microscopy also shows an increase in size and number of podocytes. The findings are diagnostic of the collapsing variant of FSGS, a lesion that is rarely seen in patients with HCV.
FINAL DIAGNOSIS Collapsing FSGS. Comment: Chronic HCV infection is increasing in the United States and
is estimated to affect 3.2 million Americans.1 Renal disease is not infrequent. In a recent study of 30 liver transplant recipients with HCV-induced cirrhosis, 12 had MPGN type 1, 7 had immunoglobin A nephropathy, 6 had mesangial proliferative glomerulonephritis, 3 had minor glomerular abnormalities, 1 had FSGS, and 1 had no disease. Interestingly, of these 30 patients, 10 had a normal serum creatinine level and 15 had normal urinalysis results. Collapsing FSGS is rare in HCV-infected patients. Most cases are associated with human immunodeficiency virus infections and the remaining are idiopathic.2 Other secondary causes of collapsing glomerulopathy include pamidronate therapy, B19 viral infection, HCV, IFN alfa treatment for hepatitis, cytomegalovirus infection, human T-cell lymphotrophic virus, and immune deficiencies. Pathogenesis is thought to involve visceral epithelial cell injury leading to podocyte dedifferentiation and detachment of these cells from the glomerular basement membrane. Clinically, there is a high proportion of blacks, high incidence of nephrotic syndrome, and rapidly progressive renal failure. Steroids, with or without cyclosporine; removal of an offending agent; blood pressure control; and lipid-lowering agents are helpful. Prognosis is poor, with rapid progression to end-stage renal disease.
American Journal of Kidney Diseases, Vol 49, No 4 (April), 2007: pp xlix-li
li
There is at least 1 case report of IFN alfa–induced collapsing FSGS in a patient who developed acute renal failure and briefly required dialysis, but recovered renal function after discontinuation of IFN therapy.3 IFN also is reported to cause the usual type of FSGS. 4 IFN therapy may cause, exacerbate, and/or ameliorate glomerular disease. Therefore, the question in this case is whether the FSGS is caused by HCV or IFN therapy. Three months after discontinuation of IFN therapy and initiation of an angiotensin receptor blocker, loop diuretic, and statin, the patient’s creatinine level decreased to 1.4 mg/dL (124 mol/L), urinary proteincreatinine ratio is 4, and edema has resolved.
REFERENCES 1. McGuire BM, Julian BA, Bynon JS Jr, et al: Brief communication: Glomerulonephritis in patients with hepatitis C cirrhosis undergoing liver transplantation. Ann Intern Med 144: 735-741, 2006 2. Laurinavicius A, Rennke HG: Collapsing glomerulopathy—A new pattern of renal injury. Semin Diagn Pathol 19:106-115, 2002 3. Stein D, Abdurhman A, Sunkhara V, Khalbuss W: Collapsing focal segmental glomerulosclerosis with recovery of renal function: An uncommon complication of interferon therapy for hepatitis C. Dig Dis Sci 46:530-535, 2001 4. Coroneos E, Petruveska G, Varghese F, Truong LD: Focal segmental glomerulosclerosis with acute renal failure associated with alpha-interferon therapy. Am J Kidney Dis 28:888-892, 1996
CASE PROVIDED BY Helen Liapis, MD1,2 and Daniel O. Young, MD,2 Departments of 1 Pathology and Immunology and 2 Internal Medicine, Renal Division, Washington University, St Louis, MO. © 2007 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2007.01.011 SUPPORT: None. POTENTIAL CONFLICTS OF INTEREST: None.
If you have an interesting case you would like to submit for consideration, please go to www.editorialmanager.com/ ajkd to do so.
Figure 1. Light microscopy (periodic acid–Schiff [PAS]; origi-
nal magnification ⫻400).
f What is your clinical differential diagnosis? f What do you see by light and electron microscopy? Figure 2.
⫻6,000).
American Journal of Kidney Diseases, Vol 49, No 4 (April), 2007: p xlix-li
Electron microscopy (original magnification
xlix
QUIZ PAGE APRIL 2007 ANSWERS DISCUSSION f What is your clinical differential diagnosis? With a history of HCV liver disease, HCV glomerulonephritis should be ruled out. Classically, glomerular disease in patients with HCV is likely to be membranoproliferative glomerulonephritis (MPGN) with cryoglobulinemia, but other glomerular diseases, such as membranous glomerulopathy, MPGN without cryoglobulinemia, diffuse proliferative and exudative glomerulonephritis, crescentic glomerulonephritis, immunoglobin A nephropathy, mesangial proliferative glomerulonephritis, and, rarely, fibrillary glomerulonephritis, are possible. f What do you see by light and electron microscopy? As seen in Fig 1, the glomerulus is remarkable for prominent podocytes covering almost the entire outer part of the capillaries. Below the proliferating podocytes, the capillary lumina are closed and the wall of the capillaries appears collapsed. There is no glomerular basement membrane duplication to suggest MPGN or mesangial cell proliferation to suggest immunoglobin A or mesangial proliferative glomerulonephritis. There are no crescents. The biopsy specimen also shows chronic inflammatory cells in the interstitium and tubular atrophy, with l
tortuous dilatation of some tubules highlighted by the PAS stain. Tubular lumens are dilated and contain PAS-positive cast material. Immunofluorescence microscopy shows sparse nonspecific deposits, but no evidence of such immune complex– mediated glomerular disease as membranous glomerulopathy. Collapsing focal segmental glomerulosclerosis (FSGS) is characterized by implosive collapse of the tuft, wrinkling and retraction of the glomerular basement membrane, podocyte hypertrophy and hyperplasia, and tubular degenerative changes. Microcystic dilatation of tubules with large and tortuous PAS-positive casts (that often have a crackledpaper appearance) are characteristic of human immunodeficiency virus–associated collapsing glomerulopathy. The electron micrograph (Fig 2) shows a partially collapsed capillary loop. Foot processes are effaced (arrow). The cytoplasm of the corresponding podocyte contains numerous cytoplasmic organelles. Typically, electron microscopy also shows an increase in size and number of podocytes. The findings are diagnostic of the collapsing variant of FSGS, a lesion that is rarely seen in patients with HCV.
FINAL DIAGNOSIS Collapsing FSGS. Comment: Chronic HCV infection is increasing in the United States and
is estimated to affect 3.2 million Americans.1 Renal disease is not infrequent. In a recent study of 30 liver transplant recipients with HCV-induced cirrhosis, 12 had MPGN type 1, 7 had immunoglobin A nephropathy, 6 had mesangial proliferative glomerulonephritis, 3 had minor glomerular abnormalities, 1 had FSGS, and 1 had no disease. Interestingly, of these 30 patients, 10 had a normal serum creatinine level and 15 had normal urinalysis results. Collapsing FSGS is rare in HCV-infected patients. Most cases are associated with human immunodeficiency virus infections and the remaining are idiopathic.2 Other secondary causes of collapsing glomerulopathy include pamidronate therapy, B19 viral infection, HCV, IFN alfa treatment for hepatitis, cytomegalovirus infection, human T-cell lymphotrophic virus, and immune deficiencies. Pathogenesis is thought to involve visceral epithelial cell injury leading to podocyte dedifferentiation and detachment of these cells from the glomerular basement membrane. Clinically, there is a high proportion of blacks, high incidence of nephrotic syndrome, and rapidly progressive renal failure. Steroids, with or without cyclosporine; removal of an offending agent; blood pressure control; and lipid-lowering agents are helpful. Prognosis is poor, with rapid progression to end-stage renal disease.
American Journal of Kidney Diseases, Vol 49, No 4 (April), 2007: pp xlix-li
li
There is at least 1 case report of IFN alfa–induced collapsing FSGS in a patient who developed acute renal failure and briefly required dialysis, but recovered renal function after discontinuation of IFN therapy.3 IFN also is reported to cause the usual type of FSGS. 4 IFN therapy may cause, exacerbate, and/or ameliorate glomerular disease. Therefore, the question in this case is whether the FSGS is caused by HCV or IFN therapy. Three months after discontinuation of IFN therapy and initiation of an angiotensin receptor blocker, loop diuretic, and statin, the patient’s creatinine level decreased to 1.4 mg/dL (124 mol/L), urinary proteincreatinine ratio is 4, and edema has resolved.
REFERENCES 1. McGuire BM, Julian BA, Bynon JS Jr, et al: Brief communication: Glomerulonephritis in patients with hepatitis C cirrhosis undergoing liver transplantation. Ann Intern Med 144: 735-741, 2006 2. Laurinavicius A, Rennke HG: Collapsing glomerulopathy—A new pattern of renal injury. Semin Diagn Pathol 19:106-115, 2002 3. Stein D, Abdurhman A, Sunkhara V, Khalbuss W: Collapsing focal segmental glomerulosclerosis with recovery of renal function: An uncommon complication of interferon therapy for hepatitis C. Dig Dis Sci 46:530-535, 2001 4. Coroneos E, Petruveska G, Varghese F, Truong LD: Focal segmental glomerulosclerosis with acute renal failure associated with alpha-interferon therapy. Am J Kidney Dis 28:888-892, 1996
CASE PROVIDED BY Helen Liapis, MD1,2 and Daniel O. Young, MD,2 Departments of 1 Pathology and Immunology and 2 Internal Medicine, Renal Division, Washington University, St Louis, MO. © 2007 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2007.01.011 SUPPORT: None. POTENTIAL CONFLICTS OF INTEREST: None.
If you have an interesting case you would like to submit for consideration, please go to www.editorialmanager.com/ ajkd to do so.