Mamdouh Albaqumi*,
Timothy J. Soos*,
Laura Barisoni and
Peter J. Nelson*
* Division of Nephrology and Department of Pathology, New York University School of Medicine, New York, New York
Address correspondence to: Dr. Peter J. Nelson, Division of Nephrology, NYU School of Medicine, Smilow Research Center, 522 First Avenue, New York, NY 10016. Phone: 212-263-7681; Fax: 212-263-7683; E-mail: nelsop02{at}popmail.med.nyu.edu
Collapsing glomerulopathy (CG) has become an important causeof ESRD. First delineated from other proteinuric glomerularlesions in the 1980s, CG is now recognized as a common, distinctpattern of proliferative parenchymal injury that portends arapid loss of renal function and poor responses to empiric therapy.Notwithstanding, the rise in disorders that are associated withCG, the identification of the first susceptibility genes forCG, the remarkable increase in murine modeling of CG, and promisingpreclinical testing of new therapeutic strategies suggest thatthe outlook for CG as a poorly understood and therapeuticallyresistant renal disease is set to change in the future. Thisfocused review highlights recent advances in research into thepathogenesis and treatment of CG.
The growing recognition in the past 25 yr of collapsing glomerulopathy(CG) as an important cause of ESRD is ascribed to both trueincreases in its incidence and detection bias. The first casesin the literature trace back to HIV-negative patients who underwentbiopsy in 1979 (1). However, antecedent descriptions of a strikinglysimilar "malignant" focal segmental glomerulosclerosis (FSGS)and of glomerular lesions with podocyte hyperplasia and retractionof the glomerular basement membrane (GBM) suggest that CG likelyexisted before 1979 (2–5). This historical detection biasas a result of a lack of recognized nosology for CG contrastswith the true expansion of CG that occurred after the onsetof the HIV pandemic, leading HIV-associated nephropathy (HIVAN),the term most often used for CG in HIV-positive patients, tobecome a major cause of ESRD (reviewed in references [6–8]).
Multiple clinicopathologic analyses of retrospectively collectedcohorts of HIV-negative and HIV-positive patients substantiatedthe hypothesis that a distinct pattern of proliferative parenchymalinjury rather than any specific associated disorder is responsiblefor the higher incidence of the nephrotic syndrome in CG versusFSGS at presentation, followed by renal replacement therapyin 50% of patients as early as <1 yr but not beyond 2 yrlater (1,9–18). By light microscopy, the glomerular filtrationbarrier that is formed by podocytes, the GBM, and the fenestratedcapillary endothelium is altered profoundly (Figure 1) (19,20).Hyperplastic and hypertrophic podocytes (i.e., "pseudocrescents,"which differ pathologically from true crescents in that theformer are composed of large epithelioid cells that resembleimmature podocytes, extend from the glomerular tuft toward Bowman’scapsule, and do not contain fibrin) overlay segmentally or globallycollapsed capillary loops, structural changes that can existbefore the development of any significant glomerulosclerosis(19,20). Importantly, however, glomerulosclerosis often is presentin conjunction with the collapse of capillaries at the timeof pathologic diagnosis, and many consider CG to be a distinctstructural form of FSGS, describing the glomerular lesion asthe "collapsing variant of FSGS" or "collapsing FSGS" (19–21).Collapse of one capillary loop is diagnostic for CG by the Columbiaclassification scheme (20,21). Ultrastructurally, podocytesshow effacement of foot processes, swelling or disappearanceof primary processes, and loss of the actin-based cytoskeleton.The underlying GBM is wrinkled and folded with subocclusionof capillary lumens (19,20). Extensive tubulointerstitial diseaseoften is present as well, and aberrant proliferation of tubularepithelium can lead to microcystic transformation along anysegment of the nephron (19,20,22). This often is accompaniedby a dense cellular infiltrate within the interstitium thatis composed largely of mononuclear phagocyte lineages, CD4+lymphocytes, and CD8+ lymphocytes (19,20,23).
Figure 1. Histopathologic and ultrastructural features of collapsing glomerulopathy. (A) A silver-stained section from a human kidney biopsy showing global collapse of the capillary tuft and pronounced podocyte hyperplasia and hypertrophy (i.e., a "pseudocrescent") that is filling Bowman’s space. The arrows point to the silver-stained remnants of the capillary tuft. (B) The tubulointerstitium from the same biopsy of A shows microcysts that contain proteinaceous casts. (C) Electron micrograph that contains a normal glomerular capillary from a wild-type C57BL/6 mouse. Note the normal thickness and contour of the glomerular basement membrane (GBM) and the well-preserved podocyte foot processes. (D) Electron micrograph of a collapsed glomerular capillary from a C57BL/6 kd/kd mouse with CG. Note the folding and wrinkling of the GBM with subocclusion of the capillary lumen marked by *. Podocytes show pronounced foot process effacement. (E) Immunohistochemical nuclear staining for Ki-67, a marker of cell-cycle progression, is absent within this normal glomerulus from a wild-type C57BL/6 mouse. (F) Expression of Ki-67 is detected clearly within glomerular epithelial cells that are forming a pseudocrescent in this diseased glomerulus from a C57BL/6 kd/kd mouse with CG. Magnifications: x400 in A and B; x25,000 in C and D; x400 in E and F. C through F reprinted from reference (73), with permission.
Unlike other podocytopathies, the podocyte injury in CG is characterizedby a marked dysregulation of the quiescent podocyte phenotype(24–34). Diseased podocytes exhibit a loss and gain ofmarkers of differentiation and proliferation, respectively,and podocytes have been described to "transdifferentiate" towarda macrophage-like cell (Table 1). Recent studies indicate thatparietal epithelial cells also may be recruited into the viscerallylocated proliferative lesion (35,36). This suggests that distinctpathogenic mechanisms may induce the pattern of glomerular injuryin CG. Indeed, whereas a decrease in the number of podocytes(i.e., "podocytopenia") within diseased glomeruli plays an importantearly role in the progression of some other structural formsof FSGS (19,20), research to determine what causes the oppositepattern of hyperplastic epithelial injury in CG have providedinsights into the pathogenesis and potential treatment of CG(discussed next).
One outcome from the growing awareness of CG as a distinct patternof proliferative parenchymal injury has been the exponentialincrease in reporting its association with disorders other thanHIV or as idiopathic (Table 2). This expanding literature likelyrepresents a greater overall trend in the diagnosis of CG. Whenbroadly categorized, these reported disorders fall into sixareas: Infections (herein includes poorly defined febrile illnesses)(12,13,37–46), autoimmune diseases (13,47–51), malignancies(13,52–54), genetic disorders (55–58), drug exposures(59–63), and during the posttransplantation period (64–70).Not surprising, wide-ranging hypotheses for the pathogenesisof CG have been posited over the years on the basis of thisgrowing list, and no one definable pathogenic trigger for CGhas emerged clearly from examining these disparate disordersas a group.
Table 2. Disorders other than HIV-1 infection that are associated with CGa,b
Nonetheless, clinical correlates do exist within these associateddisorders, which may provide important clues to the pathogenesisof CG, as follows. First, as initially recognized by Laurinaviciusand Rennke (19), most associated disorders involve a perturbationin immune homeostasis, thereby suggesting some role for immuneactivation in the development of CG. It is interesting thatmany involve T helper type 1 responses, an immune deviationthat already is known to exacerbate and accelerate other proliferativeparenchymal renal diseases (71), particularly crescentic glomerulonephritis,a glomerular lesion that is defined by the presence of truecrescents rather than by "pseudocrescents" (72). Second, althoughnot as pronounced as in HIVAN (6–8) or as in previousreports on idiopathic CG (18), patients of African descent aredisproportionately represented in Table 2, particularly amongassociated disorders that are known to activate immune responses.As a percentage of the total number of patients listed, 50%are African, 33% are white, 10% are Hispanic, and 7% representother races. Therefore, as with HIV (6–8), some of theseassociated disorders may unmask some genetic susceptibilityto develop CG, underscoring the need to identify responsiblegenes for preventive, diagnostic, prognostic, and possibly therapeuticinterventions. Finally, because the first mutant genes thatwere mapped by forward genetics to cause susceptibility to CGin humans (Table 2) and in animals (Table 3) directly impairmitochondrial function (56,73), the question arises whethermitochondria in general may lie within a common pathogenic pathwayfor CG. For example, by acting as the major cellular organellemediating many apoptotic insults (74), mitochondrial releaseof cytochrome C within renal epithelium that is affected byvarious disorders could be a common early event in the developmentof CG. Clearly, further studies are needed to support or refuteany multifactorial causation for CG that is invoked by theseclinical correlates.
The pathogenesis of CG is an area of intensive research anda focus of healthy debate. As mentioned above, this inquiryis challenged further by the growing list of associated disorders.Certainly, one promising advancement in research into the pathogenesisof CG has been the development of >10 independent murinemodels of CG within the past 15 yr (Table 3). Unlike in humans,the initial pathogenic insult or susceptibility to disease isknown in nearly every model, and its role plus the subsequentsteps in the development and progression of disease can be readilyinvestigated in vivo. When broadly categorized, CG occurs inthese models secondary to four different initiators, namely,HIV-1 gene products (75–80), Ig (81–83), oxidativestress (73,84–86), and alterations in podocyte autocrineor paracrine function (87). Collectively, these murine modelsoffer the unique opportunity to address a central question aboutthe pathogenesis of CG: How do such seemingly different insultslead to the same pattern of proliferative parenchymal injury?In other words, is there a "best-fit" model for the pathogenesisof CG? Furthermore, each model raises the possibility that atrue equivalent exists in humans.
The first recognized and propagable model of CG, the Tg26 transgenicmouse, was fortuitously discovered while transgenic techniqueswere being applied in mice to identify any pathologic featuresof HIV-1 infection that are linked to the postintegration phaseof the HIV-1 life cycle (75). This led to the hypothesis thatHIV-1 gene products directly induce HIVAN (6–8), and severalindependent laboratories have worked since then to delineatethrough murine modeling which specific HIV-1 gene products,infected cellular compartments (e.g., lymphoid versus nonlymphoid),and host-derived co-factors ultimately are responsible for mediatingHIVAN (22,75–82,88–107). Despite intensive effortsover several years, no clear consensus on these questions hasbeen reached yet among investigators. Moreover, this inquirywill need to consider the recent finding of an extensive dendriticcell network in intimate communication with the renal parenchymain normal kidney (108). Dendritic cells are important mediatorsof HIV-related diseases in many lymphoid and nonlymphoid tissues,contain several mechanisms of HIV infectivity, can harbor infectiousHIV viral particles for prolonged periods, and can provide HIVgene products (e.g., tat, nef, vpr) to and transenhance HIVinfection (e.g., tight junction synapse formation) of neighboringcells, among other pathogenic activities (109).
A second fortuitous discovery that led to the hypothesis thatIg may induce CG was the recognition of CG in mice that receivedinjections of sheep polyclonal antibodies that were raised againsttotal glomerular protein (i.e., both the cellular and the extracellularfractions) from rabbits (81), a technique that can expose miceto antibody that is directed against species-conserved epitopeson podocytes. This was the first model to show that extensiveantibody-mediated damage to podocytes can recruit epitheliumfrom the parietal surface of Bowman’s capsule into theviscerally located proliferative lesion in mice (81). This antibody-inducedCG later was recapitulated by models using mAb that were directedagainst one neo-antigen ectopically expressed on podocytes (82,83).It is interesting that rats were found recently to develop CGafter receiving serum Ig from some patients with CG (110). Couldcell-associated factors on podocytes, perhaps as a result ofmolecular mimicry or epitope spreading, be targets of autoantibodiesin some patients who develop CG, for example, in patients withsystemic lupus erythematosus or in patients with recurrent CGafter renal transplant?
Not all models have resulted from introducing genes or antibodiesinto small animals, and three models, the kd/kd mouse (73),the p53R2 null mouse (84,85), and the Dahl salt-sensitive rat(86), are genetically susceptible to CG secondary to oxidativestress–induced injury to renal parenchyma. The geneticcause for this susceptibility is known for the first two models,whereas a genetic reason for why Dahl salt-sensitive rats candevelop CG along with other glomerular lesions has not beenreported. If human equivalents for these susceptibility genesexist, then interventions to decrease environmental stress couldaffect the development or progression of CG in patients whoharbor these genes. A proof of this concept has been demonstratedalready in kd/kd mice, in which caloric restriction or birthinginto a germ-free environment rather than a specific pathogen-freeenvironment ameliorates CG in this model (111).
Eventually, as dysregulation of podocytes ensues in CG, thephysiologic, trophic autocrine (112,113), or paracrine (114,115)interaction of vascular endothelial growth factor (VEGF) withpodocytes or with capillary endothelium, respectively, willbe disrupted. Although the exact point at which this occursis speculative, its potential role in the pathogenesis of CGwas discovered by directly overexpressing a specific VEGF isoformin mouse podocytes in vivo (87). These mice develop global collapseof the capillary tuft, suggesting that injury to podocytes witha concomitant change in their normal autocrine or paracrinefunction likely contributes to the development of CG. Whetheraberrant VEGF signaling, either by changes in VEGF productionor by alterations in VEGF receptor signal transduction, in theabsence of any previous insult to podocytes initiates CG inhumans is unknown.
How could these different insults lead to the same pattern ofproliferative parenchymal injury if, paradoxically, the initialphenotypic response of renal epithelium that seems to be sharedin common across insults is apoptosis or necrosis? One potentialanswer to this question comes from recent studies to determinewhy death of some epithelial cells leads to hyperplasia andtransformation of adjacent epithelium rather than normal repairin some disease states (Figure 2). These studies found thatthe integration of external cues that are produced via apoptoticor necrotic epithelium by adjacent epithelium, particularlyin inflammatory microenvironments, renders the adjacent epitheliumpoorly responsive to cellular controls that would normally limitproliferation (116,117). As a result, the parenchymal phenotypethat is most evident after initiation of disease is hyperplasia.This has clear pathophysiologic consequences because the contributionfrom dying epithelial cells to the loss of organ function becomesgreatly amplified by the additional loss of cellular functionfrom proliferating and dedifferentiated epithelium that surroundsthe initial sites of injury. Although this speculative "bestfit" model has not been investigated directly in CG, preliminarystudies to characterize the earliest stages of development ofCG in some murine models have found that apoptosis or necrosisof renal epithelium occurs before the aberrant proliferationof renal epithelium becomes apparent (80,84,85,94,118).
Figure 2. A speculative "best-fit" model for the pattern of parenchymal injury in collapsing glomerulopathy. (A) Within the pictured epithelial monolayer, an intrinsic or extrinsic apoptotic or necrotic insult to discrete epithelial cells is communicated to surrounding epithelial cells and resident innate immune cells. Rather than induce normal repair or cytostasis by adjacent epithelial cells, a proinflammatory, nontolerogenic response promotes aberrant hyperplasia. This eventually will progress to fibrosis and atrophy of the injured parenchyma. Factors within the lumen and preexisting states of immune deviation also may contribute to creating this mitogenic and fibrogenic microenvironment. (B) The consequence of this aberrant hyperplastic response within specific compartments of the kidney is to disrupt structure–function relationships that are required for normal nephron function. Within the glomerulus, proliferating, dedifferentiated podocytes and recruited parietal epithelium cannot contribute to the glomerular filtration barrier or to the maintenance of patent capillary loop structures. Within the tubulointerstitium, this aberrant hyperplastic response manifests as microcystic transformation.
No evidence-based therapy exists for CG, and current therapeuticstrategies derive from the empiric approach that CG may be treatedby analogy to other renal diseases or associated disorders (119–121).Not surprising, then, the current recommendations for how totreat CG are based on anecdote, retrospect, and expert opinion(119–121). The leading recommendations for the treatmentof CG in non–HIV-infected patients suggest drug regimensthat are used to treat FSGS (119,120). Table 4 lists patients’renal outcomes from all reports that have analyzed retrospectivelythe therapeutic response of CG in HIV-negative patients whowere treated by analogy to FSGS (1,12,13,15,16,119,122). Althoughthe drugs, dosage, duration of treatment, and definition oftherapeutic response vary among studies, it is clear that areport of full remission (9.6% of all patients treated) or partialremission (15.2% of all patients treated) altogether was infrequent.Likewise, the recommended first-line therapy for CG in HIV-positivepatients is highly active antiretroviral therapy (HAART) totarget the associated disorder, HIV-1 infection (121). One estimatethat was calculated from retrospectively collected data fromthe Centers for Disease Control and Prevention and the US RenalData System found that the rate of progression of CG to ESRDin HIV-positive patients may be slowed by as much as 38% withthe use of HAART (123). Although hopeful, a recent analysisof renal outcomes in a large multicenter study of HIV-positivepatients with CG that was diagnosed and treated in the post-HAARTera reported a need for renal replacement therapy in 50% ofthe cohort by approximately 390 d (13 mo) after presentation(124). Therefore, given the lack of treatments that can inducedurable remission in the majority of all patients with CG, thereis a clear need for new therapeutic strategies.
Table 4. Renal outcomes after treatment of CG in HIV-negative patients
Physiologic structure–function relationships within thekidney require the presence of quiescent, differentiated renalparenchyma, and one therapeutic strategy that has demonstratedpreservation of renal function in preclinical studies in animalsis to induce growth arrest of aberrantly proliferating renalepithelium (125). Small molecule inhibitors of the cyclin-dependentkinases that control cell-cycle progression in renal epitheliumcan prevent and reverse experimental CG from different insults(126–129). Likewise, experimental CG can be amelioratedby retinoic acid derivatives that activate retinoic acid receptors,transcription factors that inhibit mitogenesis signaling andupregulate genes that promote differentiation of renal epithelium(130). It is interesting that small molecule inhibitors of inflammatorypathways that are controlled by NF-B and cyclooxygenase-2 alsohave improved renal function in experimental CG (86,131), highlightingthe multifactorial basis for the proliferative phenotype inCG. Taken together, these preclinical studies signal that rationalapproaches to therapy for CG on the basis of knowledge of pathogenesisrather than of empiricism may be on the horizon.
Much progress has been made in research into the pathogenesisand treatment of CG during the past two decades. The growingawareness of the diagnostic criteria for CG has increased thereporting of associated disorders, thereby contributing to clinicalcorrelates that may stimulate research into causative mechanismsfor CG. This inquiry is aided by the identification of the firstsusceptibility genes for CG and the explosive growth in murinemodeling of CG, each providing important insights into the pathogenesisof CG. Finally, the success of preclinical testing of new therapeuticstrategies on the basis of knowledge that already has been gainedfrom studies in humans and animals holds promise that CG willnot herald poor outcomes for patients in the future.
Acknowledgments
M.A. is supported by a Research Fellowship Award from the AmgenNephrology Institute. T.J.S. is supported by a Pilot ProjectAward from the National Institutes of Health Center for AidsResearch grant AI027742. P.J.N. is supported by National Institutesof Health grant DK065498.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Abstract
History and Clinicopathologic...
B and cyclooxygenase-2 also have improved renal function in experimental CG (86,131), highlighting the multifactorial basis for the proliferative phenotype in CG. Taken together, these preclinical studies signal that rational approaches to therapy for CG on the basis of knowledge of pathogenesis rather than of empiricism may be on the horizon. 
