Collapsing Glomerulopathy: A Cause of ...

4 downloads 45065 Views 113KB Size Report
... renal failure and pulmonary edema. © 2002 by the National Kidney Foundation, Inc. ..... 537-547, 1999. 33. Markowitz GS, Appel GB, Fine PL, et al: Collapsing.
CASE REPORT

Collapsing Glomerulopathy: A Cause of Noncardiogenic Pulmonary Edema Michael R. Wiederkehr, MD, Thomas E. Rogers, MD, and Orson W. Moe, MD ● Collapsing glomerulopathy is a pathologic diagnosis characterized by obliteration of glomerular capillary lumina, seen most commonly as a primary glomerular disease in young black men. A secondary form with almost identical pathologic features is described in association with human immunodeficiency virus infection. The disease is characterized by heavy proteinuria with variable renal insufficiency at the onset followed by rapid progression to end-stage renal disease with no documented effective therapy. We describe a patient who presented with systemic manifestations, including fever, acute renal failure with massive proteinuria, and noncardiogenic pulmonary edema. Renal biopsy showed classic collapsing glomerulopathy. All known causes of noncardiogenic pulmonary edema were ruled out. The pulmonary syndrome resolved, but the renal disease progressed to end-stage renal disease. We propose consideration of collapsing glomerulopathy in the differential diagnosis of any patient presenting with a multisystem disease including acute renal failure and pulmonary edema. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: Collapsing glomerulopathy (GN); pulmonary-renal syndrome; proteinuria; renal failure.

C

OLLAPSING glomerulopathy classically was described as a primary glomerular disease with distinctive clinical and pathologic features typically in young and middle-aged black men.1-9 Clinically, patients present with heavy proteinuria with variable degrees of renal insufficiency.1-8 The pathologic hallmark of the disease is focal segmental glomerulosclerosis with distinguishing collapsing obliteration of glomerular capillaries. Similar morphologic features can be seen in secondary glomerular diseases, such as human immunodeficiency virus (HIV)–associated glomerulopathy, collagen vascular disease, and certain systemic infections.6,9-18 Collapsing glomerulopathy also exists as a primary renal disorder without systemic involvement. The only extrarenal manifestations of the disease have been variable degrees of constitutional symptoms, such as malaise and fever. The natural course of primary collapsing glomerulopathy is universal progression to end-stage renal disease with no documented effective therapy.1,4-6 In contrast to the conventional description of the disease, we describe an HIV-negative patient with typical collapsing glomerulopathy on renal biopsy who presented with nephrotic proteinuria, acute renal insufficiency, and pulmonary infiltrates. All other causes of pulmonary infiltrates with acute renal failure were ruled out. The pulmonary syndrome remitted, but the renal disease progressed to end-stage renal stage. Collapsing glomerulonephritis should be included in the

differential diagnosis of patients who present with renal failure, proteinuria, and pulmonary infiltrates. CASE REPORT The patient is a 35-year-old healthy athletic black man with no significant medical history until he presented with an influenza-like illness of malaise and lethargy. This condition developed in a few days to arthralgia involving knees and elbows, myalgia of proximal and distal muscles, and fever of 104°F. The musculoskeletal and constitutional symptoms were followed rapidly by bilateral pedal edema, cough, and dyspnea on exertion. He was admitted to the hospital 3 weeks after the onset of his illness. He denied any previous illness or use of any prescription, over-the-counter, or illicit drugs. Examination revealed a young black man in distress with a respiratory rate of 20 breaths/min, heart rate of 140 beats/min, blood pressure of 170/100 mm Hg, and tempera-

From the Departments of Internal Medicine and Pathology, Department of Veterans Affairs Medical Center and University of Texas Southwestern Medical Center, Dallas, TX. Received September 17, 2001; accepted in revised form May 9, 2002. Supported by the National Institutes of Health (DK48482 and DK-54396), Department of Veterans Affairs Research Service, the American Heart Association Texas Affiliate (98G-052), and the National Kidney Foundation of Texas. Address reprint requests to Orson W. Moe, MD, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8856. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 1523-6838/02/4003-0032$35.00/0 doi:10.1053/ajkd.2002.34935

American Journal of Kidney Diseases, Vol 40, No 3 (September), 2002: E10

1

2

ture of 103°F. Diffuse muscle tenderness and bilateral lower extremity pitting edema were noted. No active joint or skin lesions were present. All pulses were palpable. Funduscopic examination was normal. Auscultation revealed normal heart sounds and bilateral basilar inspiratory crackles. Neurologic examination was normal. Initial laboratory tests revealed a white blood cell count of 22.4 (4% lymphocytes, 1.3% monocytes, 94% granulocytes, 15% neutrophils with eosinophils and basophils ⬍0.5%); a normocytic normochromic anemia with a hematocrit of 36; plasma creatinine, 2.0 mg/dL; blood urea nitrogen, 40 mg/ dL; creatine kinase, 927 U/L with negative MB fraction; lactate dehydrogenase, 685 U/L; serum albumin, 3.0 mg/dL; and normal electrolytes, liver parenchymal enzymes, amylase, lipase, and prothrombin and partial thromboplastin times. Arterial blood gas analysis showed pH 7.51; PCO2, 28 mm Hg; and PO2, 49 mm Hg while breathing room air with an alveolar-arterial gradient of about 50 mm Hg. Electrocardiogram showed sinus tachycardia but was otherwise within normal limits. Chest radiograph showed bilateral basilar infiltrates (Fig 1). A urine toxicology screen was negative (including cocaine). Urinalysis showed greater than 1,000 mg/dL protein but was completely negative for cells or casts on repeated occasions. Urinary eosinophils were absent. A 24-hour urine collection on admission showed 30 g of protein and 22 mg/kg of creatinine. The patient rapidly deteriorated to respiratory arrest requiring intubation and mechanical ventilation. Before intubation, arterial blood gases while rebreathing 100% oxygen was pH 7.32; PCO2, 32 mm Hg; and PO2, 42 mm Hg, indicating a severe shunt. Swan-Ganz catheterization revealed pulmonary artery pressure of 24/15 mm Hg (systolic/diastolic), pulmonary capillary wedge pressure, 9 mm Hg; cardiac output, 6.3 L/min; cardiac index, 3.1 L/min/m2; stroke volume, 81.8 mL; and calculated systemic vascular resistance, 800 Ds/ cm5. The hemodynamic picture was consistent with noncar-

WIEDERKEHR ET AL

diogenic pulmonary edema. Echocardiogram showed normal cardiac chambers and valves with well-preserved systolic ventricular function. A pulmonary ventilation-perfusion scan was indeterminate. A pulmonary angiogram was normal. Bronchial washings were negative for malignant cells and Gram stain and specifically negative for Pneumocystis carinii, acid-fast bacilli, and Legionella. Cerebrospinal fluid was normal in cell count and chemistry. All bronchial, blood, cerebrospinal fluid, and urine cultures were negative. Plasma serologies were negative for antinuclear antibody, rheumatoid factor, anti–glomerular basement membrane antibody (enzyme-linked immunoassay), antineutrophil cytoplasmic antibody (ANCA) (IgG and IgM by flow cytometry, ANCA pattern by immunofluorescence assay), antimyeloperoxidase, antiproteinase-3, antistreptolysin O, and antibody against influenza A (1:8), parainfluenza (1:4), adenovirus (0), Chlamydia (0), Rickettsia (0), cytomegalovirus (0), respiratory syncytial virus (1:4), Histoplasma (0), Blastomyces (0), Aspergillus (0), Mycoplasma (1:8), varicella (1:4), and Q fever (0). One cryoglobulin was reported as 1⫹ but was negative on several subsequent repeats. All cryoglobulins were collected with appropriate 37°C preservation at the bedside. Serologies for HIV and hepatitis B were negative. The only positive serum serology was anti–hepatitis C antibody. Serum C3 complement was within normal limits. There was one slightly low C4 complement of 8 mg/dL along with numerous C4 measurements within normal range. Computer tomography scan and magnetic resonance imaging of the head, thorax, abdomen, and pelvis were negative other than the pulmonary infiltrates noted earlier. During the first week of hospitalization, the patient became progressively more oliguric, and plasma creatinine rose to 5.5 mg/dL. The unstable clinical status precluded renal biopsy at the time. Electromyogram was compatible with myositis, and a muscle biopsy specimen showed mild nonspecific myopathic changes with type II myofiber atro-

Fig 1. Chest radiograph on admission.

COLLAPSING GN AND PULMONARY-RENAL SYNDROME

phy but no evidence of myositis. The patient was started on broad-spectrum antibiotics, and hemodialysis was initiated. An empirical trial of corticosteroids was given consisting of three 1-g methylprednisolone intravenous pulses followed by 1 mg/kg of intravenous methylprednisolone for 4 days and the same dose of oral prednisone thereafter. Over the next 7 days, the pulmonary infiltrates and hypoxemia resolved; the patient stabilized and was extubated but remained dialysis-dependent. With resolution of the critical respiratory status, a percutaneous renal biopsy was performed.

Biopsy Findings The renal biopsy specimen contained medulla and cortex containing eight glomeruli. The low-power view showed mild-to-moderate degree of acute tubulointerstitial infiltrate. There were occasional focal areas of tubular epithelial regeneration and tubular calcification. There was no evidence of interstitial edema. The main pathology was in the glomeruli. Three of the eight glomeruli were globally sclerosed. Figure 2 shows the glomerular pathology. Four of the remaining five showed segmental sclerosis characterized by collapse of capillary loops around the mesangial region in the involved glomerular tufts. There was no evidence of mesangial expansion or hypercellularity in the glomeruli. The areas of segmental sclerosis were associated with variable degrees of epithelial cell hyperplasia. This finding is compatible with the literature, which describes prominent hyaline droplets and coarse vacuoles in the hyperplastic epithelial cells early in collapsing glomerulonephritis.1-8 The epithelial cell hyperplasia associated with this variant of segmental sclerosis becomes less prominent as sclerosis progresses.1-8 There was no evidence of vasculitis in the biopsy specimen. Immunofluorescence was negative; specifically, direct immunofluorescence was negative for IgA and other immunoglobulins and complement components. Ultrastructural analysis, although highlighting the collapse of

Fig 2. A glomerulus showing segmental sclerosis with collapse of capillary loops around the mesangial region in the involved tuft and hypertrophy and hyperplasia of the overlying visceral epithelium. (Periodic acid–Schiff, original magnification ⴛ250.)

3

glomerular capillary tufts and hypertrophy of podocytes, failed to show any evidence of electron dense deposits or other glomerular abnormalities.

Clinical Outcome Three weeks after the renal biopsy, the patent had a urine output of 800 to 900 mL/d and a predialytic plasma creatinine of 4 mg/dL corresponding to an endogenous creatinine clearance of 17 mL/min and a urea clearance of 11 mL/min. Hemodialysis was withheld, and the patient remained asymptomatic other than mild peripheral edema. Chest radiograph and arterial blood gases were completely normal by this time. After 2 months of prednisone therapy, his proteinuria remained greater than 20 g/d. Prednisone was tapered, and the patient was managed with diltiazem and captopril. Over the next 4 months, his plasma creatinine gradually rose to 8.5 mg/dL. An iothalamate clearance done at this time revealed a glomerular filtration rate of 9 mL/min. Hemodialysis was initiated via a forearm arteriovenous fistula. The patient remained medically stable on long-term hemodialysis except for one episode of acute monarthritis with crystalnegative and culture-negative purulent synovial fluid. Two years after initiation of long-term hemodialysis, the patient was evaluated for but was rejected from cadaveric renal transplantation because of psychological reasons. The patient remained stable on hemodialysis and had no further recurrence of pulmonary symptoms or muscular complaints for 4 years after the initial presentation.

DISCUSSION

The diagnosis of collapsing glomerulopathy was not considered initially in this young black patient with proteinuria because of the unusual features of pulmonary edema and myalgia accompanying azotemia and nephrotic proteinuria. All

4

WIEDERKEHR ET AL Table 1.

Differential Diagnosis of Acute Renal Failure With a Pulmonary Infiltrate Transudative Infiltrate (Pulmonary Edema) High Pressure

Glomerular disease

Renal sodium retention

Low Pressure

Sepsis with ARDS and immune complex GN Renal/deep vein thrombosis with pulmonary emboli

Interstitial disease

Renal sodium retention

Hemodynamic renal failure

Renal sodium retention LV pump failure Tamponade Renal sodium retention

Toxin-related renal failure

Sepsis with ARDS and allergic interstitial nephritis Sepsis with ARDS and ATN

Rhabdomyolysis “Crack lung” Sepsis with ARDS and drug-induced ATN

Exudative Infiltrate (Leukocytes ⫾ Erythrocytes)

Anti-GBM disease Vasculitides: Wegener’s Churg-Strauss Collagen vascular diseases with GN Renal or deep vein thrombosis with pulmonary emboli/infarction Pneumonia with immune complex GN (eg, Mycoplasma) Collagen vascular disease (eg, lupus, Sjo¨gren’s)

Pneumonia with rhabdomyolysis (eg, influenza, Legionella) Paraquat ingestion

Abbreviations: ARDS, Adult respiratory distress syndrome; GN, glomerulonephritis; GBM, glomerular basement membrane; ATN, acute tubular necrosis; LV, left ventricular.

existing literature of collapsing glomerulopathy indicates absence of systemic involvement other than mild nonspecific constitutional symptoms.1-8 The classic differential diagnoses for a patient presenting with acute renal failure, pulmonary infiltrates and systemic manifestations typically highlight Goodpasture’s (anti–basement membrane) disease, systemic vasculitides such as Wegener’s syndrome and Churg-Strauss syndrome, and collagen vascular diseases such as systemic lupus erythematosus.19-21 The importance of these diagnoses cannot be overemphasized because most of these diseases are universally progressive and often fatal if appropriate intervention is not initiated in due time. When most clinicians encounter a patient with a constellation of these findings, however, anti–basement membrane disease and systemic vasculitides account for only a few cases. A broader and more utilitarian differential diagnosis is presented in Table 1. This list is by no means exhaustive, but it illustrates an approach to any patient acutely presenting with a pulmonary infiltrate and any renal abnormality, including azotemia and abnormal urinalysis. There are two advantages to this list. First, it highlights the more commonly encountered conditions. The most common cause of acute renal failure and a pulmonary infiltrate is

probably hemodynamic renal failure and left ventricular pump failure. Second, this list is more complete than what is usually presented in textbooks so that the clinician would consider some of the less frequent causes. A subclassification based on the nature of the pulmonary and renal abnormalities, if available, helps to restrict the diagnostic options and streamlines the evaluation. There are conditions that are not classically associated with a pulmonary infiltrate but on rare occasions can present as such; this includes fibrillary glomerulonephritis and thrombotic thrombocytopenic purpura.22,23 We propose adding collapsing glomerulopathy to this list. The two most salient features of our patient’s presentation were pulmonary edema and massive proteinuria, both of which rapidly deteriorated to respiratory and renal failure. The low pulmonary capillary wedge pressure and normal echocardiogram excluded cardiac causes. Although there was massive proteinuria, the plasma albumin concentration was well maintained at 3 g/dL on presentation. The pulmonary edema was not due to imbalance of Starling hydrostatic and oncotic driving forces but rather was due to increased permeability. Even when plasma albumin falls to extremely low levels, hypoalbuminemia as a sole cause of pulmonary edema is

COLLAPSING GN AND PULMONARY-RENAL SYNDROME

exceedingly rare.24 The absence of a systemic infection, disseminated intravascular coagulation, exposure to noxious inhaled substances, drug overdose such as narcotics, thoracic trauma, central nervous system disorder, and pulmonary embolism practically rules out all other known causes of adult respiratory distress syndrome. The renal pathology was characteristic for collapsing glomerulopathy. There was segmental sclerosis with collapse of the capillary loops in the involved tufts around the mesangial region, absence of mesangial hypercellularity or mesangial matrix expansion, and variable degrees of visceral epithelial cell hypertrophy and hyperplasia. Secondary causes of this pathologic lesion have been described.6,9-18 Our patient was HIVnegative6,9,14,15; did not have evidence of a collagen vascular disease,6 a hematologic malignancy,6 or a previous renal transplant16-18; and resided in urban Dallas, where he was unlikely to have contact with Leishmania or Filaria.12,13 The patient was hepatitis C antibody–positive, however. There was one equivocal cryoglobulin result and one low C4, neither one of which was reproducible on repeat measurements. In addition to membranoproliferative and membranous glomerulonephritis, the scope of glomerular lesions associated with hepatitis C has ranged from mild mesangial proliferation to fibrillary and crescentic proliferative glomerulonephritis.25,26 There were no other indications of our patient having a systemic vasculitis, and the renal biopsy was not compatible with vasculitis. Laurinavicius et al6 described three patients with serologic positive hepatitis C and characteristic collapsing glomerulopathy on renal biopsy. It is difficult to ascertain whether our patient’s collapsing glomerulopathy was linked to hepatitis C. Regardless, the presentation in this patient is unique because neither primary collapsing glomerulopathy nor the hepatitis C–associated variant has been described with noncardiogenic pulmonary edema. Our patient also had clinical, biochemical, and histologic evidence of muscle injury. The initial presentation of rhabdomyolysis and pulmonary infiltrate prompted a high index of suspicion for influenza or Legionella. There was no serologic or microbiologic evidence of either of these infectious agents, however. The patient also had high fevers without an identifiable infectious

5

source. The resolution of the fever was coincidental with empirical broad-spectrum antibiotic coverage and high-dose corticosteroid therapy. The systemic disease resolved, whereas the renal abnormalities persisted. The loss of renal function was relentless, culminating in end-stage renal disease approximately 6 months after presentation. This rapid downhill course is typical for collapsing glomerulopathy. To this date, no therapy has been shown to be effective in collapsing glomerulonephritis. Only a few retrospective and uncontrolled analyses of treatment regimens have been published. Steroids, with or without cyclophosphamide or cyclosporine, have achieved partial or complete remissions in only a few cases, but some patients had spontaneous remission without therapy.1,2,4 Our patient already showed advanced disease: Only one of eight glomeruli had no sclerosis or collapse of capillary loops, proteinuria was 30 g/d, and serum creatinine was 2 mg/dL. Considering the uncertain benefit and adverse sideeffect profile of cytotoxic therapy, in particular, in hepatitis C positivity, we decided on steroid therapy only, with reevaluation at 8 weeks. He had ongoing massive proteinuria of 20 g/d at week 8, and we initiated a steroid taper. His creatinine clearance decreased from 17 to 9 mL/ min between weeks 3 and 16. It is unlikely that the 8-week course of oral prednisone significantly influenced the patient’s clinical course or that a more prolonged treatment would have been more successful. The cause of collapsing glomerulopathy is unknown. Several investigators independently postulated that the collapsing lesion may be a primary disorder of the podocyte.27-32 Abnormalities of the podocyte have been described in patients with primary collapsing glomerulopathy. The fact that a similar morphologic finding can be seen in association with diverse underlying conditions such as HIV, hepatitis C, collagen vascular disease, parasitic infection, and renal transplant suggests that this may be a final common pathway by which the glomerular podocyte responds to certain insults. The idiopathic forms of collapsing glomerulopathy may represent cases in which the inciting agents have not been identified yet. Recurrence of collapsing glomerulopathy in the allograft also is compatible with a systemic factor. The report by Markowitz et al33

6

WIEDERKEHR ET AL

describing collapsing glomerulopathy in patients treated with bisphosphonates indicated that the systemic administration of a drug can incite this lesion in the kidney. It is conceivable that whatever systemic factors injure the podocyte also can affect the pulmonary capillaries. The noncollapsing variant of primary focal segmental glomerulosclerosis could be caused by a circulating permeability factor that remains to be identified.34 In conclusion, the pathologic diagnosis of collapsing glomerulopathy can be a primary renal disease, or it can be associated with other systemic diseases. The cause of this morphologic lesion in the glomerulus is unknown, but it is conceivable that the collapsing lesion may be a glomerular reaction to diverse insults. Collapsing glomerulopathy can present as a systemic disease and should be included in the differential diagnosis of acute renal failure with pulmonary infiltrates. REFERENCES 1. Weiss MA, Daquioag E, Margolin EG, Pollak VE: Nephrotic syndrome, progressive irreversible renal failure, and glomerular “collapse”: A new clinicopathologic entity? Am J Kidney Dis 7:20-28, 1986 2. Detwiler RK, Falk RJ, Hogan SL, Jennette JC: Collapsing glomerulopathy: A clinically and pathologically distinct variant of focal segmental glomerulosclerosis. Kidney Int 45:1416-1424, 1994 3. Haas M, Spargo BH, Coventry S: Increasing incidence of focal segmental glomerulosclerosis among adult nephropathies: A 20 year renal biopsy study. Am J Kidney Dis 26:740-750, 1995 4. Valeri A, Barisoni L, Appel GB, Seigle R, D’Agati V: Idiopathic collapsing focal segmental glomerulosclerosis: A clinicopathologic study. Kidney Int 50:1734-1746, 1996 5. Grcevska L, Polenakovik M: Collapsing glomerulopathy: Clinical characteristics and follow-up. Am J Kidney Dis 33:652-657, 1999 6. Laurinavicius A, Hurwitz S, Rennke HG: Collapsing glomerulopathy in HIV and non-HIV patients: A clinicopathological and follow-up study. Kidney Int 56:2203-2213, 1999 7. Avila-Casado MC: Collapsing glomerulopathy: A new entity associated with nephrotic syndrome and end-stage renal failure. Rev Invest Clin 51:367-373, 1999 8. Singh HK, Baldree LA, McKenney DW, Hogan SL, Jennette JC: Idiopathic collapsing glomerulopathy in children. Pediatr Nephrol 14:132-137, 2000 9. Shahinian V, Rajaraman S, Borucki M, Grady J, Hollander WM, Ahuja TS: Prevalence of HIV-associated nephropathy in autopsies of HIV-infected patients. Am J Kidney Dis 35:884-888, 2000

10. Madiwale C, Venkataseshan VS: Renal lesions in AIDS: A biopsy and autopsy study. Indian J Pathol Microbiol 42:45-54, 1999 11. Cheng JT, Anderson HL Jr, Markowitz GS, Appel GB, Pogue VA, D’Agati VD: Hepatitis C virus–associated glomerular disease in patients with human immunodeficiency virus co-infection. J Am Soc Nephrol 10:1566-1574, 1999 12. Leblond V, Beaufils H, Ginsburg C, et al: Collapsing focal segmental glomerulosclerosis associated with visceral leishmaniasis. Nephrol Dial Transplant 9:1353, 1994 13. Pakasa NM, Nseka NM, Nyimi LM: Secondary collapsing glomerulopathy associated with Loa Loa filariasis. Am J Kidney Dis 30:836-839, 1997 14. D’Agati V, Cheng JI, Carbone L, Cheng JT, Appel G: The pathology of HIV-nephropathy: A detailed morphologic and comparative study. Kidney Int 35:1358-1370, 1989 15. Stokes MB, Chawla H, Brody RI, et al: Immune complex glomerulonephritis in patients coinfected with human immunodeficiency virus and hepatitis C virus. Am J Kidney Dis 29:514-525, 1997 16. Meehan SM, Pascual M, Williams WW, et al: De novo collapsing glomerulopathy in renal allografts. Transplantation 65:1192-1197, 1998 17. Clarkson MR, O’Meara YM, Murphy B, Rennke HG, Brady HR: Collapsing glomerulopathy—recurrence in a renal allograft. Nephrol Dial Transplant 13:503-506, 1998 18. Stokes MB, Davis CL, Alpers CE: Collapsing glomerulopathy in renal allografts: A morphological pattern with diverse clinicopathologic associations. Am J Kidney Dis 33:658-666, 1999 19. Young KR Jr: Pulmonary-renal syndromes. Clin Chest Med 10:655-675, 1989 20. Niles JL, Bottinger EP, Saurina GR, et al: The syndrome of lung hemorrhage and nephritis is usually an ANCA-associated condition. Arch Intern Med 156:440-445, 1996 21. Bosch X, Font J: The pulmonary-renal syndrome: A poorly understood clinicopathologic condition. Lupus 8:258262, 1999 22. Rovin BH, Bou-Khalil P, Sedmak D: Pulmonaryrenal syndrome in a patient with fibrillary glomerulonephritis. Am J Kidney Dis 22:713-716, 1993 23. Panoskaltsis N, Derman M, Perillo I, Brennan JK: Thrombotic thombocytopenic purpura in pulmonary renal syndrome. Am J Hematol 65:50-55, 2000 24. Buehler BA: Hereditary disorders of albumin synthesis. Ann Clin Lab Sci 8:283-286, 1978 25. Jefferson JA, Johnson RJ: Treatment of hepatitis C-associated glomerular disease. Semin Nephrol 20:286292, 2000 26. Pouteil-Noble C, Maiza H, Dijoud F, MacGregor B: Glomerular disease associated with hepatitis C virus infection in native kidneys. Nephrol Dial Transplant 15:28-33, 2000 (suppl 8) 27. Kriz W: The role of the podocyte in the degeneration of a renal glomerulus. Adv Nephrol Necker Hosp 27:1-13, 1997 28. Kihara I, Tsuchida S, Yaoita E, et al: Podocyte detach-

COLLAPSING GN AND PULMONARY-RENAL SYNDROME

ment and epithelial cell reaction in focal segmental glomerulosclerosis with cellular variants. Kidney Int Suppl 63:S171S176, 1997 29. Bariety J, Nochy D, Mandet C, Jacquot C, Glotz D, Meyrier A: Podocytes undergo phenotypic changes and express macrophage-associated markers in idiopathic collapsing glomerulopathy. Kidney Int 53:918-925, 1998 30. Nagata M, Hattori M, Hamano Y, Ito K, Saitoh K, Watanabe T: Origin and phenotypic features of hyperplastic epithelial cells in collapsing glomerulopathy. Am J Kidney Dis 32:962-969, 1998 31. Barisoni L, Kriz W, Mundel P, D’Agati V: The dysregulated podocyte phenotype: A novel concept in the pathogenesis of collapsing idiopathic focal segmental glomer-

7

ulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 10:51-61, 1999 32. Kihara I, Yaoita E, Kawasaki K, Yamamoto T, Hara M, Yanagihara T: Origin of hyperplastic epithelial cells in idiopathic collapsing glomerulopathy. Histopathology 34: 537-547, 1999 33. Markowitz GS, Appel GB, Fine PL, et al: Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol 12:1164-1172, 2001 34. Savin VJ, Sharma R, Sharma M, et al: Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 334:878-883, 1996