* 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
Correspondence: Dr Laura Barisoni, Department of Pathology, New York University School of Medicine, 560 First Avenue, New York, NY 10016; Phone: 212-263-5422; Fax: 212-263-0783; e-mail: barisl01{at}med.nyu.edu
Collapsing glomerulopathy is a proliferative disease definedby segmental or global wrinkling of the glomerular basementmembranes associated with podocyte proliferation. These lesionsare particularly poor responders to standard therapies. Firstdescribed as an idiopathic disorder or following HIV infection,it is now associated with a broad group of diseases and differentpathogenetic mechanisms, which participate in podocyte injuryand mitogenic stimulation. Because of this etiologic heterogeneity,there is clear need for new therapeutic approaches to targeteach variant of this entity. Historical background, terminology,morphologic and phenotypic features, and suggested mechanismsare reviewed in this manuscript.
A 20-yr-old black woman was healthy until 4 weeks before admissionwhen she developed gastric discomfort, nausea, and occasionalvomiting, followed by progressive edema of lower extremities.On admission she was afebrile and normotensive and physicalexamination was unremarkable. Urinalysis showed 3+ protein (8g/24 h), 0 to 2 red blood cells/hpf, 2 to 5 white blood cells/hpf,and occasional granular casts. The serum creatinine was 1.4mg/dl at presentation and increased to 1.8 mg/dl during hospitalization;blood urea nitrogen was 11 mg/dl, total protein 4.4 g/dl, albumin2.0 g/dl. The hematocrit was 43% at presentation but decreasedto 34% in the following weeks. Hepatic function was normal.Serology for hepatitis B and C, HIV, rapid plasma reagin, andantinuclear antibody was negative. Serum complement was withinthe normal range.
A renal biopsy contained 35 glomeruli, two obsolescent. Mostglomeruli displayed segmental or global glomer-ular collapse(Figure 1, a and b). Focal neutrophilic tubulitis, granularand Tamm-Horsfall casts, acute tubular injury with scatteredmildly dilated tubules, and moderately severe interstitial inflammationwere also noted. Immunofluorescence showed nonspecific stainingfor IgM and C3 in the areas of collapse (Figure 1c). The lightmicroscopy findings were confirmed by ultrastructural analysis(Figure 1d). The morphologic findings were classic for collapsingglomerulopathy (CG; Table 1). Given the patient's history ofa recent virus-like syndrome, infection for parvovirus B19 (PVB19)was suspected and confirmed by high IgG and IgM titers. Thefinal diagnosis was CG associated with active PVB19 infection.
Figure 1. (a) segmental collapse of the glomerular basement membranes (blue arrows) with occlusion of the capillary lumina. Podocytes are hyperplastic and hypertrophic and form pseudo-crescents (red arrows). Pseudo-crescents are generally separated from parietal epithelium by the urinary space (silver stain, original magnification x40). (b) This enlarged detail of another glomerulus shows that some podocytes adjacent a collapse segmental of the tuft acquire a bizarre shape and contain large smudgy nuclei (red arrows) (silver stain). Despite the presence of these features, immunohistochemistry analysis for PBV was negative (not shown). (c) Nonspecific immunofluorescence staining for C3 in an area of collapse. (d) Electron microscopy shows a collapsed glomerular lobule (white arrow). Podocytes have a cubical appearance, and no primary of foot processes are seen (black arrow). Podocytes are separated from the underlying collapsed glomerular basement membranes by interposition of newly formed extracellular matrix (white asterisk).
Table 1. Morphologic features of collapsing glomerulopathy (CG)
The patient was discharged with stable creatinine at 1.8 mg/dl.Immunosuppression was avoided, and she was started on intravenousIg. A few weeks later, her symptoms improved, the IgM titersdecreased, and polymerase chain reaction for PVB19 was negative.Her edema resolved 4 mo after onset, suggesting remission. Shewas lost to follow-up for a year, after which she presentedwith renal failure. The patient started hemodialysis and waslisted for renal transplantation.
CG is now recognized as a common, distinct pattern of "proliferative"parenchymal injury with poor response to empiric therapy. Thefirst description of the disease appeared in 1978 and named"malignant focal segmental glomerulosclerosis" (FSGS) becauseof rapidly progressive nephrotic syndrome.1 In the early 1980s,during the HIV pandemic, CG was a relatively frequent diagnosisin large cities of the east and west coasts of the United Statesand "HIV-associated nephropathy" was the common term to identifythe injury. In 1986, Weiss et al. described a similar renallesion in HIV-negative patients with severe proteinuria andrapid progression to renal failure, and the term "collapsingglomerulopathy" was used for the first time to indicate this"new clinical-pathologic entity."2 The relationship betweenidiopathic CG and FSGS was officially introduced in the literatureby Detwiler et al. who suggested that CG was a variant of FSGS,3a concept reinforced by a second clinical study, where the diseasewas termed "idiopathic collapsing FSGS."4
Although the term "collapsing FSGS" has been largely used sincethe mid 1990s, a growing number of authors prefer to use theterm "collapsing glomerulopathy." This preference may have clinicalrelevance. The term "FSGS" indicates segmental solidification(sclerosis) of the tuft with adhesion to Bowman's capsule. CG,on the other hand, is defined by collapse and pseudo-crescentformation. The mechanism by which the podocytes are injuredis also distinct: proliferation characterizes CG, whereas podocytopeniais implicated in the pathogenesis of FSGS.5 Thus, it is notsurprising that CG is resistant to standard therapies used forFSGS. Experimental CG can be ameliorated or reversed by inhibitingproliferation or promoting differentiation as shown with inhibitorsof cyclin-dependent kinesis or retinoic acid derivatives.1 Incontrast, some forms of experimental FSGS ameliorate after replacementtherapy with stem cells.6
Another term, "cellular lesion," was also introduced in the1980s to identify this entity.7 The recently proposed Columbiaclassification suggests using "cellular lesion" for glomerulopathiescharacterized by hypercellularity in the intracapillary compartment,in contrast to "collapsing lesions," where the glomerular tuftappears hypocellular, and increased cellularity is limited tothe urinary space.8
The reporting of CG in the literature has increased with thegrowing awareness among nephrologists and pathologists of itsassociation with disorders other than HIV.1 A recently proposedtaxonomy for the podocytopathies classifies CG apart from FSGSand recognizes three major categories: idiopathic, genetic,and secondary or reactive (Table 2).5
Table 2. Classification of collapsing glomerulopathy (CG)
Numerous hypotheses for the pathogenesis of CG have been generated,but no specific common trigger for epithelial cell proliferationhas emerged. The spectra of clinical associations and etiologicfactors is broad and the observation, in some cases, that perturbationof the immune system may occur suggests some role for immuneactivation in the development of CG.9
The prevalence of the disease in blacks suggests a genetic susceptibility,1,3,4,10and the identification of mutations in the chromosome encodingfor CoQ2 in a European family11 and for prenyltransferase-likemitochondrial protein in the kd/kd mouse,12 further corroboratesthis hypothesis. The mechanism by which podocytes react to malfunctioningmitochondria by undergoing proliferation rather than apoptosisis not fully clear. By analogy with a model of myocardial ischemicinjury, one could speculate that ion channels in the inner membranesof mitochondria may mediate protection of cells from death.Ion channels have a potential role in redox regulation and mediationof activation of the transcription factor, hypoxia induciblefactor-1.13 Hypoxia inducible factor-1 has been shown to modulatepodocyte phenotype and induce proliferation.14 Modulation ofthe redox state of mitochondria is mediated by environmentalfactors and involved in the onset and progression of the disease.15The administration of amino-bisphosphonates, a known cause ofCG,is also likely to cause mitochondrial degeneration. Theseobservations suggest that disruption of mitochondrial functionalityin general may represent a common pathophysiological mechanismin CG.16
In addition to HIV, other infectious diseases are associatedwith CG (Table 2). The mechanism of podocyte injury followingHIV infection may be direct, with intracellular expression ofviral genome or proteins, and/or indirect, mediated by releaseof cytokines by inflammatory cells in the circulation or inthe renal parenchyma (Figure 2).1 PVB19 infection is associatedwith podocyte injury in patients with CG, minimal change disease,and FSGS.17–19 The detection of PVB19 in renal epithelialcells by immunostaining and in situ hybridization suggests,similar to HIV-associated disease, a direct cytopathic effect.17The specific relationship between CG and PVB19 infection remainscontroversial, and the pathogenesis remains unknown. But becausethe spectrum of manifestation of PVB19 infection range fromasymptomatic to fatal in immunocompromised individuals,20 itis prudent to investigate causes of CG in cases otherwise categorizedas "idiopathic" before using immunosuppressive therapy. Thecase here presented is in support of the clinical associationbetween PVB19 infection and CG: the systemic symptoms of viralinfection preceded the renal disease; they were followed bydecreased hematocrit, and the viral infection was confirmedby positive serology for active/acute phase and detection ofthe viral DNA by PCR.
Figure 2. Pathophysiology of podocyte proliferation and collapsing glomerulopathy. Several mechanisms are involved in the pathophysiology of CG. Two major common pathways have been identified: activation of the immune system and dysregulation of mitochondrial activity. In addition, both genetic susceptibility and environmental factors play a major role in modulating the pathogenetic process. Solid arrows indicate mechanisms that have been already investigated, and the dotted arrows indicate potential pathways to be investigated.
Other proposed mechanisms of podocyte injury include dysregulationof vascular endothelial growth factor expression and acute ischemicprocesses, such as thrombotic microangiopathy after therapywith calcineurin inhibitors.21 Alterations of intracellularmetabolism after the use of certain medications, or cytopathiceffects due to accumulation of light chains, have also beenimplicated (Figure 2).1 Some of these forms can be reversedif the inducing agent is eliminated.22 Lessons from experimentalmodels of CG23 and the rapid recurrence of CG after transplantationin some patients indicate that a yet to be identified permeabilityfactor should be included in the list of causative agents (Table 2).24
CG is not only a glomerular or podocyte disease, but all renalepithelial cells may be affected. Direct cytopathic damage byviral products also occurs in tubular cells and results in increasedproliferation, apoptosis, and translocation of specific proteinsfrom basolateral location to apical location.25 Tubular celldamage may also be secondary to released cytokines by the increasedinflammatory cell in the interstitium. These events translateinto acute and chronic tubular injury and microcyst formation.The degree of tubulointerstitial damage varies from case tocase and appears more pronounced in those forms where intrinsicepithelial cell damage, such as viral infection, is known tobe the pathogenetic factor (personal observation, L.B.).
PODOCYTE PHENOTYPE AND THE CELLULAR ORIGIN OF THE PSEUDO-CRESCENTS
In CG, podocyte injury results in dedifferentiated phenotype,reflected by the loss of expression of maturity markers andreexpression of proliferative markers; dysregulation of thephenotype, reflected by loss of expression of WT-1; and trans-differentiationtoward a macrophage-like phenotype5 (Table 3). The degree ofdedifferentiation and dysregulation varies between subclassesof CG and appears less prominent in some of the secondary/reactiveor genetic forms compared with idiopathic and HIV-associatedforms (Table 4).
Table 4. Critical pathologic features to differentiate subcategories of collapsing glomerulopathy (CG)
Although the epithelial cells forming pseudo-crescents are thoughtto originate from podocytes, the theory of the dysregulatedpodocyte has been recently challenged. Some authors suggestthat pseudo-crescents are formed by parietal epithelial cells,based on 2 observations: the presence of bridging cells betweenBowman's capsule and the pseudo-crescents and positive stainingfor CK and PAX2.26 Against these arguments is that immatureor developing podocytes express PAX2 and transiently CKs (Table 3).Bridging of parietal epithelial and parietal podocytes is anormal event occurring in nondiseased kidney.27 Studies on aninducible model of podocyte injury show bridging of parietalcells is a late event, probably representing a mechanism ofrepair resulting in sclerosis, following an early phase dominatedby proliferation.28 It is intriguing to speculate that the residentstem cells lining Bowman's capsule29 may also participate inrepair processes.
CG is a unique pattern of glomerular and tubulointerstitialinjury for which the pathologic diagnosis is based on histologicfindings, but the final diagnosis and treatment require closecollaboration between renal pathologists and nephrologists.In an era dominated by biomarkers, pathologists should participatein the development of new tools to expand standard morphologicdescriptions with information about etiology, pathogenesis,and phenotype, to guide nephrologists to identify more rationaltherapeutic approaches.
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Abstract
Introduction
