PATHOPHYSIOLOGY of the RENAL BIOPSY www.jasn.org Current Views on Collapsing Glomerulopathy Mamdouh Albaqumi* and Laura Barisoni† *King Faisal Specialist Hospital and Research Center, Department of Medicine, Section of Nephrology, Riyadh, Saudi Arabia; and †New York University School of Medicine, Department of Pathology and Medicine, Division of Nephrology, New York, New York ABSTRACT Collapsing glomerulopathy is a proliferative disease defined by segmental or mo after onset, suggesting remission. She global wrinkling of the glomerular basement membranes associated with podocyte was lost to follow-up for a year, after which proliferation. These lesions are particularly poor responders to standard therapies. she presented with renal failure. The pa- First described as an idiopathic disorder or following HIV infection, it is now tient started hemodialysis and was listed associated with a broad group of diseases and different pathogenetic mechanisms, for renal transplantation. which participate in podocyte injury and mitogenic stimulation. Because of this etiologic heterogeneity, there is clear need for new therapeutic approaches to HISTORY OF THE DISEASE AND target each variant of this entity. Historical background, terminology, morphologic TERMINOLOGY and phenotypic features, and suggested mechanisms are reviewed in this manuscript. CG is now recognized as a common, distinct J Am Soc Nephrol 19: 1276–1281, 2008. doi: 10.1681/ASN.2007080926 pattern of “proliferative” parenchymal injury with poor response to empiric therapy. The first description of the disease appeared in 1978 and named “malignant focal segmental glomerulosclerosis” (FSGS) because of rap- A 20-yr-old black woman was healthy ular collapse (Figure 1, a and b). Focal idly progressive nephrotic syndrome.1 In the until 4 weeks before admission when neutrophilic tubulitis, granular and early 1980s, during the HIV pandemic, CG she developed gastric discomfort, nau- Tamm-Horsfall casts, acute tubular in- was a relatively frequent diagnosis in large cit- sea, and occasional vomiting, followed jury with scattered mildly dilated tu- ies of the east and west coasts of the United by progressive edema of lower extrem- bules, and moderately severe intersti- States and “HIV-associated nephropathy” ities. On admission she was afebrile tial inflammation were also noted. was the common term to identify the injury. and normotensive and physical exami- Immunofluorescence showed nonspe- In 1986, Weiss et al. described a similar renal nation was unremarkable. Urinalysis cific staining for IgM and C3 in the ar- lesion in HIV-negative patients with severe showed 3ϩ protein (8 g/24 h), 0 to 2 eas of collapse (Figure 1c). The light proteinuria and rapid progression to renal red blood cells/hpf, 2 to 5 white blood microscopy findings were confirmed failure, and the term “collapsing glomeru- cells/hpf, and occasional granular by ultrastructural analysis (Figure 1d). lopathy”wasusedforthefirsttimetoindicate casts. The serum creatinine was 1.4 The morphologic findings were classic this “new clinical-pathologic entity.”2 The re- mg/dl at presentation and increased to for collapsing glomerulopathy (CG; lationship between idiopathic CG and FSGS 1.8 mg/dl during hospitalization; Table 1). Given the patient’s history of was officially introduced in the literature by blood urea nitrogen was 11 mg/dl, total a recent virus-like syndrome, infection Detwiler et al. who suggested that CG was a protein 4.4 g/dl, albumin 2.0 g/dl. The for parvovirus B19 (PVB19) was sus- variant of FSGS,3 a concept reinforced by a hematocrit was 43% at presentation pected and confirmed by high IgG and but decreased to 34% in the following IgM titers. The final diagnosis was CG weeks. Hepatic function was normal. associated with active PVB19 infection. Serology for hepatitis B and C, HIV, The patient was discharged with stable Published online ahead of print. Publication date rapid plasma reagin, and antinuclear creatinine at 1.8 mg/dl. Immunosuppres- available at www.jasn.org. antibody was negative. Serum comple- sion was avoided, and she was started on Correspondence: Dr Laura Barisoni, Department of Pa- thology, New York University School of Medicine, 560 ment was within the normal range. intravenous Ig. A few weeks later, her First Avenue, New York, NY 10016; Phone: 212-263- A renal biopsy contained 35 glomer- symptoms improved, the IgM titers de- 5422; Fax: 212-263-0783; e-mail: [email protected] uli, two obsolescent. Most glomeruli creased, and polymerase chain reaction for Copyright ᮊ 2008 by the American Society of displayed segmental or global glomer- PVB19 was negative. Her edema resolved 4 Nephrology 1276 ISSN : 1046-6673/1907-1276 J Am Soc Nephrol 19: 1276–1281, 2008 www.jasn.org PATHOPHYSIOLOGY of the RENAL BIOPSY Table 1. Morphologic features of second clinical study, where the disease was gests some role for immune activation in the collapsing glomerulopathy (CG) termed “idiopathic collapsing FSGS.”4 development of CG.9 Light microscopy Although the term “collapsing FSGS” has The prevalence of the disease in blacks Glomeruli been largely used since the mid 1990s, a suggests a genetic susceptibility,1,3,4,10 and the Collapsea: segmental or global growing number of authors prefer to use the identification of mutations in the chromo- wrinkling and folding of the GBM term “collapsing glomerulopathy.” This some encoding for CoQ2 in a European fam- with sub-occlusion or occlusion of preference may have clinical relevance. The ily11 and for prenyltransferase-like mito- the capillaries 12 a term “FSGS” indicates segmental solidifica- chondrial protein in the kd/kd mouse, Pseudo-crescents : podocyte tion (sclerosis) of the tuft with adhesion to further corroborates this hypothesis. The hyperplasia (proliferation) Bowman’s capsule. CG, on the other hand, is mechanism by which podocytes react to mal- Hypertrophic podocytes with occasional large nuclei defined by collapse and pseudo-crescent for- functioning mitochondria by undergoing Protein reabsorption droplets in mation. The mechanism by which the podo- proliferation rather than apoptosis is not fully cytoplasm of podocytes cytes are injured is also distinct: proliferation clear. By analogy with a model of myocardial Segmental and/or global sclerosis characterizes CG, whereas podocytopenia is ischemic injury, one could speculate that ion (advance phase) implicated in the pathogenesis of FSGS.5 channels in the inner membranes of mito- Tubules Thus, it is not surprising that CG is resistant chondria may mediate protection of cells Microcysts: dilated, often serpentine- to standard therapies used for FSGS. Experi- from death. Ion channels have a potential shaped, tubules with flat mental CG can be ameliorated or reversed by role in redox regulation and mediation of ac- epithelium containing eosinophilic inhibiting proliferation or promoting differ- tivation of the transcription factor, hypoxia proteinaceous casts with entiation as shown with inhibitors of cyclin- inducible factor-1.13 Hypoxia inducible fac- peripheral scalloping dependent kinesis or retinoic acid deriva- tor-1 has been shown to modulate podocyte Acute tubular injury: flattening of the 1 14 tubular epithelium, large epithelial tives. In contrast, some forms of phenotype and induce proliferation. Mod- cells, large, occasionally atypical, experimental FSGS ameliorate after replace- ulation of the redox state of mitochondria is 6 nuclei with prominent nucleoli ment therapy with stem cells. mediated by environmental factors and in- Tubular atrophy Another term, “cellular lesion,” was volved in the onset and progression of the Interstitium also introduced in the 1980s to identify this disease.15 The administration of amino- Edema entity.7 The recently proposed Columbia bisphosphonates, a known cause of CG, Inflammation classification suggests using “cellular le- is also likely to cause mitochondrial de- Fibrosis sion” for glomerulopathies characterized generation. These observations suggest Vessels by hypercellularity in the intracapillary that disruption of mitochondrial func- Nonspecific changes unless TMA- compartment, in contrast to “collapsing le- tionality in general may represent a com- associated CG Immunofluorescence sions,” where the glomerular tuft appears mon pathophysiological mechanism in 16 Nonspecific entrapment of IgM and hypocellular, and increased cellularity is CG. 8 C3 in areas of collapse limited to the urinary space. In addition to HIV, other infectious dis- Electron microscopy eases are associated with CG (Table 2). The Extensive foot process effacement mechanism of podocyte injury following Loss of detectable actin-based ETIOLOGY, CLASSIFICATION, AND HIV infection may be direct, with intracellu- cytoskeleton PATHOGENESIS lar expression of viral genome or proteins, Loss of primary processes and/or indirect, mediated by release of cyto- Large cuboidal podocytes with pale The reporting of CG in the literature has kines by inflammatory cells in the circulation cytoplasm increased with the growing awareness or in the renal parenchyma (Figure 2).1 Electron dense protein reabsorption among nephrologists and pathologists of PVB19 infection is associated with podocyte droplets in podocyte cytoplasm its association with disorders other than injury in patients with CG, minimal change Detachment of podocytes from 1 17–19 underlying GBM and interposition HIV. A recently proposed taxonomy for disease, and FSGS. The detection of of newly formed extracellular the podocytopathies classifies