Podocyte Anatomy:
Podocytes are post-mitotic cells whose function depends on their cytoarchitecture. They are composed of a cell body, primary processes and foot processes (connected to the cell body by the primary processes). The podocyte surface is divided by the slit diaphragm (SD) in the luminal surface, facing the urinary space, and abluminal surface, facing the glomerular basement membranes (GBM). Podocytes serve several functions including:

1. Regulation of permselectivity through cell-cell interaction at the level of SD
   
   
2. Structural support for the glomerular capillaries though a network of interdigitating processes
   
   
3. Counteraction the intracapillary hydrostatic pressure
   
   
4. Remodeling the GBM

1. Impaired formation of the slit diaphragm complex and its associated lipid rafts
   
   
2. Abnormalities of the adhesive interaction between podocytes and GBM
   
   
3. Alterations of transcription factors
   
   
4. Abnormalities of the actin-based cytoskeleton
   
   
5. Alterations of the apical domain of podocytes
   
   
6. Mechanical stress
   
   
7. Viral infection
   
   
8. Acute ischemic injury
   
   
9. Toxic/metabolic effect

Slit Diaphragm
SD is composed of a complex of proteins located in the extracellular space, bridging adjacent foot processes. It is composed of different proteins including: mFAT1, nephrin, the nephrin homologue Neph1, CD2AP, and podocin. The recent discovery of these proteins as part of the SD has emphasized the critical role of the SD in maintaining the normal function of the filtration barrier. The identification of the nephrin gene NPHS1 elucidated the genetic defect underlying congenital nephrotic syndrome of Finnish type. Patients lacking normal nephrin have severe proteinuria and foot process effacement at birth and rapidly develop glomerular sclerosis and ESRD. The podocyte phenotype lacks staining for nephrin on IF or immunohistochemistry and ultrastructurally shows extensive foot process effacement. The role of nephrin in maintaining the function of the filtration barrier is also demonstrated experimentally by injection of anti-nephrin Ab into animals, which resulted in proteinuria. Similarly, inactivation of NHSP1 in mice results in foot process effacement and proteinuria. Both in animal models and in humannephrotic syndrome, when foot process effacement occurs, nephrin is found redistributed in the apical (luminal) portion of the podocyte plasma membrane. Another report shows that the expression of nephrin is lower in areas of foot process effacement versus those areas where the foot processes are preserved. The question is whether immunostaining for nephrin may help to discriminate between the different forms of FSGS, MCD or CGP. Based on the available literature, the use of specific antibodies to nephrin is limited to cases of congenital nephrotic syndrome.

Mutations of NPHS2, which encodes for another protein located at the SD, podocin, are the genetic cause of autosomal recessive, steroid-resistant nephrotic syndrome in pediatric and adult populations. Podocin is localized at the insertion of the SD and interacts with both nephrin and CD2AP. It appears that podocin serves in the structural organization of the SD, acting as a scaffolding protein, hence the decrease in expression and/or distribution may influence both the cytoskeleton and the SD. Mice lacking podocin develop congenital nephrosis. Mutations in both podocin gene alleles lead to a wide range of human diseases from childhood onset steroid resistant FSGS and minimal change disease, to adult FSGS. A single report shows that children with steroid resistant and steroid sensitive nephrotic syndrome and a variety of diseases from minimal change disease, to mesangial proliferation and IgA nephropathy, have reduced expression of podocin. Moreover, this study shows a non-specific correlation between podocin expression and response to steroid therapy.

One of the most exiting recent discoveries has been made by the group of Andrew Shaw. Mice lacking CD2AP rapidly develop podocyte injury followed by mesangial sclerosis, indicating that indeed, podocytes are the primary cause of glomerular damage. So far only 2 patients with FSGS have been shown to have mutations in the gene encoding for CD2AP (unpublished data).

MFAT1 is a protein also localized in the SD and mice lacking mFAT1 exhibit perinatal mortality. So far, no human form of proteinuria has been related to mFAT1. ZO-1 is a protein localized at the insertion of the SD, but there is no described disease of the foot processes associated with a defect of ZO-1.

Abnormalities of the Adhesive Interaction Between Podocytes and GBM
Several factors contribute to maintain the highly ordered foot process architecture. Some of these proteins are localized in the SD, others are part of the actin-based cytoskeleton, and others are located at the abluminal side (sole) of podocytes. α3-β1 integrin and α- and β dystroglycan are the major proteins responsible for the adhesion of podocytes to the underlying GBM. Interesting, the integrin-binding status may influence the cytoskeleton organization and thereby contribute to determining the foot process shape. Indeed, blockage of the β1-integrin binding site by specific antibodies leads to foot process effacement, proteinuria and detachment. Also the dystroglycans, heterodimeric proteins composed of a transmembrane component (β) and an extracellular subunit (α), are connected to the actin-based cytoskeleton through urotrophin (the podocyte equivalent of dystrophin in skeletal muscle). One of the most exciting studies from a practical point of view has demonstrated that in MCD, during the proteinuric state, the expression of dystroglycan and β1-integrin is markedly reduced, whereas dystroglycan is preserved in FSGS, despite a comparable amount of proteinuria. The expression of dystroglycan and β1-integrin returns to normal once the foot processes are restored. This result is unexpected given the fact that on ultrastructural analysis, detachment of podocytes from the GBM is never observed in MCD, whereas it is a relatively common feature in FSGS. Several conclusions can be made: first, this is a phenomenon specific to steroid sensitive MCD, and may explain how proteins leak into the urinary space in the absence of visible podocyte detachment. Second, MCD and FSGS have in common foot process effacement but are two distinct diseases and some additional pathomechanisms must be responsible for podocyte detachment in FSGS. The relationship between MCD and FSGS has been controversial. Some cases with a diagnosis of steroid resistant MCD at the first biopsy have a diagnosis of FSGS at the second biopsy, raising the question whether these cases are FSGS, where the segmental lesion has not been sampled. Or do these specific cases represent a form of MCD that progresses to FSGS? The use of markers such as dystroglycan may help discriminate true MCD, from early FSGS.

Alterations of Transcription Factors
Three major transcription factors appear important in podocytopathies: Wilm's tumor 1 (WT-1), PAX2, and LMX1B. WT-1 is selectively expressed in mature podocytes, whereas WT-1 is expressed in all cells during development. PAX2 gene encodes a transcription factor expressed early during development and is a WT-1 target gene. Therefore, when glomeruli mature and WT-1 expression increases and is restricted to podocyte only, PAX2 expression decreases. Both these factors are very important for metanephric development. WT-1 expression is altered in congenital and acquired glomerular diseases. Among the congenital disorders Denys-Drash syndrome and Fresier syndrome should be mentioned. Denys-Drash syndrome is characterized by early onset of nephrotic syndrome, male pseudohermaphroditism, and neuroblastoma. The glomerular lesions are diffuse mesangial sclerosis, accompanied by podocyte hypertrophy and proliferation. Podocyte phenotype is characterized by loss of expression of WT-1 by immunostaining with increased expression of PAX2 and proliferative markers such as Ki67. Interestingly, in collapsing glomerulopathy, which is not characterized by mesangial sclerosis but by collapse of the glomerular capillaries and podocyte proliferation with pseudocrescents formation, WT-1 expression is decreased in collapsed and non-collapsed glomeruli. PAX2 and Ki67 expression are up-regulated, indicative of podocyte de-differentiation and re-entry into the cell cycle.

Nail patella syndrome is an autosomal dominant disease characterized by proteinuria, skeletal abnormalities, and nail hypoplasia, and is due to defect in LMX1B. LMX1B regulates the expression of several podocyte genes critical for podocyte differentiation and function. The real mechanism of this disease is still unclear. LMX1B-/- podocytes have reduced number of foot processes, are dysplastic, and lack typical SD. These unique findings indicate an arrest in development, however, they have normal levels of nephrin, synaptopodin, ZO-1, and α-3 integrin.

Abnormalities of the Actin-based Cytoskeleton
The actin-based cytoskeleton of foot processes contains numerous proteins and the most important in this context are α-actinin-4 and synaptopodin. There are 3 different recognized podocyte phenotypes in regard to cytoskeleton reorganization or expression. It is well known that in nephrotic syndrome, and this is particularly evident in MCD but also in FSGS, reorganization of the actin-based cytoskeleton occurs, and intermediate filaments are observed condensed against the "sole" of podocytes, rather than sparsely distributed in the cytosol. In these conditions, no significant alteration of the cytoskeletal protein expression has been described. On the contrary, in certain forms of autosomal dominant FSGS, mutations of the gene encoding for α-actinin-4 have been found. This disease is highly but not fully penetrant, leading to proteinuria and renal insufficiency in adulthood. The mutant actinin shows higher affinity for F-actin. α-actinin-4 deficient mice are different from mouse models deficient in nephrin, WT-1, or podocin, and do not have nephrosis at birth but develop it later in life later in life, as in human disease. This indicates that alterations in α-actinin-4 lead to podocyte damage and FSGS by causing subtle cytoskeletal changes. Of note, mice lacking synaptopodin, another component of the cytoskeleton, do not have any specific phenotype and foot process effacement and sclerosis occurs only after partial nephrectomy. These data indicate that there is probably a compensatory mechanism within the cytoskeleton if any of the components are missing, but podocytes are more prone to injury. The question is whether α-actinin-4 staining can be used as a useful marker to identify this form of autosomal dominant FSGS or potential sporadic forms in adults. Although this aspect needs to be further investigated, immunostaining does not appear to be particularly useful. Quantification of intraglomerular mRNA, after laser capture microdissection has shown positive correlation forthe expression levels of ACTN4, GLEPP-1, synaptopodin, dystroglycan,WT-1, and nephrin in acquired proteinuric diseases, but the expression of a single protein was not predictive of disease.

The other important component of the cytoskeleton is synaptopodin. Synaptopodin expression has been shown to be markedly reduced in CGP, whereas it is generally well preserved in MCD and FSGS. In particular, synaptopodin expression is not only reduced in the collapsed glomeruli, but also in the non-collapsed ones, indicating that in certain forms of CGP, the podocyte injury precedes the glomerular damage.

Alterations of the Apical Domain of Podocytes
On the luminal side, podocytes are equipped with a well-developed glycocalyx, having a negative charge, mostly composed of podocalyxin. Podocalyxin is expressed in both podocytes and endothelial cells early during development. Podocalyxin is of critical importance for the formation and preservation of cell architecture. Podocalyxin knock out mice have flattened podocytes. GLEPP-1, a transmembrane protein tyrosine phosphate inserted in the luminal surface of podocytes, may also have an important role in regulating structure and function of podocytes. In human diseases, it has been demonstrated that the expression of both podocalyxin and GLEPP-1 is markedly reduced in FSGS, in areas of sclerosis, which is expected since no podocytes should be present in those areas, and in areas of podocyte hypertrophy and hyperplasia (pseudocrescents) in CGP. Of note, podocalyxin expression is well preserved in endothelial cells, indicating that indeed CGP is a podocyte disease.

Mechanical Stress
FSGS can be idiopathic, secondary to genetic defects affecting proteins that are part of the cytoskeleton or the SD, or secondary to mechanical stress. The latter mechanism is involved in those forms of FSGS due to hyperfiltration (single kidney, obesity, hypertension, and others). There is in vivo and in vitro evidence of the role of podocyte stretching in the development of "secondary" FSGS. First, lessons from the animal models teach us that FSGS develops after significant ablation of renal parenchyma. It has been suggested that segmental sclerosis is preceded by increased in glomerular area (glomerulomegaly), and accompanied by mechanical stretching of podocytes. Podocytes are post-mitotic cells and, with the only exception of collapsing glomerulopathy and Denys-Drash syndrome, they cannot proliferate. Therefore, under mechanical stress, podocytes react by undergoing hypertrophy to maintain their function as the filtration barrier and attempt to cover a larger surface of GBM, by reorganization of the actin-based cytoskeleton. This leads to foot process effacement, focal detachment with pseudocyst formation, to complete detachment and death (podocyturia), and GBM are left "denuded". This step is a point of non-return to synechia formation (adhesion of the GBM to the Bowman capsule). It has been suggested that parietal cells migrate from the Bowman capsule to cover the naked GBM. In vitro, this phenomenon has been confirmed and has been shown that, once podocytes are mechanically stretched, they undergo reorganization of the actin-based cytoskeleton but not alteration of expression of podocyte proteins. The change in phenotype is restricted to morphologic variation in size and shape but not protein expression. Moreover, mechanically stretched podocytes re-enter the cell cycle, do not proliferate but undergo hypertrophy. In human disease, it has been demonstrated that glomerulomegaly occurs in secondary forms of FSGS, e.g. hypertension- or obesity-mediated. In these forms no change in podocyte phenotype has been described except for focal foot process effacement.

Viral Infection
Viral infection has been considered the cause of some forms of CGP. Patients with collapsing glomerulopathy should be tested for HIV, parvovirus B19, SV40 and CMV (one case only in the literature). Both HIV and parvovirus B19 mRNA have been demonstrated in podocytes and epithelial cells in biopsies form patients with CGP. The podocyte phenotype in these diseases is not only de-differentiated, but also trans-differentiated and dysregulated. Podocytes lose their foot processes along with primary processes and assume a cuboidal shape, which resembles immature podocytes. Moreover, the expression of specific podocyte maturity markers, podocalyxin, GLEPP-1, CALLA, is down-regulated (de-differentiation). De-differentiation is accompanied by re-entry of the cell cycle and proliferation, which is reflected by the positive staining for Ki-67 in areas of pseudocrescent formation. Podocytes acquire properties of other cell lines and express CK and CD68 (trans-differentiation), and simultaneously lose molecules, which are expresses at any developmental stage, such as WT-1 (dysregulation), with consequent up-regulation of PAX2. This phenomenon has also been confirmed in animal models of HIV-1 infection, where podocyte damage, reflected by the up-regulation of desmin expression, occurs early during the disease, when the HIV-1 mRNA can be demonstrated in podocytes. This is accompanied by attenuation of synaptopodin expression, and followed by sclerosis, pseudocrescents formation, complete loss of synaptopodin and WT-1, and Ki-67 expression. In the HIV model of CGP, two major fragment of the HIV genome have been implicated in the pathogenesis of the renal disease: Nef and Vpr. We recently created a model of glomerular collapse/sclerosis where Vpr expression is driven by podocin as promoter. Once Vpr is activated, mice develop proteinuria, podocyte hypertrophy and hyperplasia, and later glomerulosclerosis.

Acute Ischemic Injury
CGP was initially described in association with HIV infection and called HIV-associated nephropathy (HIV-AN) or as an idiopathic form. More recently new form of CGP have been described in addition to the virus-associated ones, and they appear to be due to a reactive process to acute ischemia rather than a primary podocyte injury. Frequently pathologists encounter cases with glomerular collapse and pseudocrescents formation in transplant biopsies. Whereas some of these cases may represent a recurrent disease, in other cases no history of collapsing glomerulopathy prior to the transplant is present. In many of these biopsies, thrombotic microangiopathy (TMA) can be demonstrated. The pathomechanism involved in these forms is still unknown, and podocyte changes may be considered reactive to ischemia. It is interesting to speculate that VEGF-mediated cross talking between podocytes and endothelial cells may occur and play a role in the pathomechanism. The question is whether we have any biomarker to discriminate between the reactive and primary form of podocyte injury and collapse. Synaptopodin and WT-1 may be useful markers. Whereas in viral-associated CGP, the loss of synaptopodin is global and diffuse not only in the affected glomeruli, but also in the non-affected ones, preliminary studies show that in reactive forms of collapsing glomerulopathy, loss of synaptopodin is restricted to the affected glomeruli.

Toxic/Metabolic Effect
Recently, CGP has been associated with a variety of diseases (myeloma, Still's disease, tuberculosis, and others) or use of medications such as pamidronate or interferon. Medications also cause podocyte injury without proliferation and collapse, and those include pamidronate, interferon and NSAID. The pathogenetic mechanism underlying these subgroups of CGP is different: in pamidronate-associated disease it has been suggested that the toxic effect of pamidronate is mediated by GTPase, impairment of cell energy via ATPase, and disruption of the cytoskeleton. In CGP associated with myeloma, Still's disease or tuberculosis it is possible that the process is mediated by inflammatory mediators (interferon?). Moreover, interferon-induced CGP has also been reported. It has to be mentioned that in all these reports viral infection has not been excluded, and although most of the patients are HIV negative, none of them have been tested for parvovirus B19. Moreover, pamidronate-associated podocyte injury has been described also in few cases of MCD. Studies are still in progress to better characterize the podocyte phenotype in these patients. We recently presented a limited study including patients with idiopathic, TMA-associated and pamidronate-associated collapsing glomerulopathy. Cases were stratified based on the presence or absence of synaptopodin expression in the non-affected glomeruli. We found that, whereas the pamidronate-associated cases behave as "reactive" CGP, and synaptopodin expression was preserved in non-collapsed glomeruli, among the cases with proven or suspected TMA and idiopathic forms, the podocyte phenotype varied from diffusely de-differentiated and dysregulated to "reactive pattern". Studied with antibodies against parvovirus B19 need to be done to exclude a virus-mediated process in those cases that present with dysregulated phenotype.

Considering this new knowledge on podocyte phenotype, the next logical step would be to try to re-classify well-known morphologic entities, previously identified based on histologic features. Although the morphology remains the guide to identify the major subgroups of podocytopathies (MCD, FSGS and CGP), additional information, including podocyte phenotype and detailed clinical history, may be helpful to sub-classify these entities, learn more about prognosis and better target the therapy in each sub-group.

Proposed Scheme for Work Up of Renal Biopsies with Podocytopathies

1. Steroid sensitive MCD = 100% foot process effacement + dystroglycan staining
   
   
2. Steroid resistant MCD = 100% foot process effacement + dystroglycan staining (positive?), + nephrin staining (if CNS is suspected), + podocin staining (variable)
   
   
3. Congenital nephrotic syndrome = 100% foot process effacement + nephrin staining
   
   
4. Mesangial sclerosis =WT-1, PAX2 and Ki-67
   
   
5. Idiopathic FSGS = Extensive foot process effacement +? synaptopodin, podocin staining
   
   
6. Familial FSGS = variable degree of foot process effacement + podocin, nephrin, α-actinin-4.
   
   
7. Secondary FSGS = glomerulomegaly + <50% foot process effacement +clinical history of HTN or obesity.
   
   
8. Collapsing glomerulopathy = collapse and pseudocrescents + Hx of viral infection and/or staining for parvovirus B19 + synaptopodin + WT-1 + PAX2, + Ki-67

Classification of Podocytopathies

Histology	Pathologic variant	Pathogenetic factor
Normal	Acquired MCD	?Dystroglycan
	Drug induced	NSAID, pamidronate, interferon
	Genetic defect	Nephrin, podocin, ?19q13
Mesangial sclerosis	DDS & FS	WT 1
	Sporadic forms MS	WT 1
Focal segmental glomerulosclerosis	Idiopathic	Unknown
	Permeability factor	Unknown
	Genetic defect	Podocin,α-actinin-4, TRPC6, LMX1B, ?19q13 , CD2AP
	Hyperfiltration-associated	Mechanical stress
Collapsing glomerulopathy	Idiopathic	Unknown
	Virus-associated	HIV; parvovirus B19; SV40; CMV
	Infectious diseases	leishmaniasis; filariasis; TB
	Secondary to ischemia	TMA; severe vasculopathy
	Drug-induced	Pamidronate, interferon
	Autoimmune disease	?
	Genetic defect	?

Selected References
Reviews

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2. Barisoni L, Kopp JB. Update in podocyte biology: putting one's best foot forward. Curr Opin Nephrol Hypertens. 2003 May;12(3):251-8. Review.
   
   
3. Barisoni L, Mundel P. Podocyte biology and the emerging understanding of podocyte diseases. Am J Nephrol. 2003 Sep-Oct;23(5):353-60. Epub 2003 Aug 12. Review.
   
   
4. Schachter AD. The pediatric nephrotic syndrome spectrum: clinical homogeneity and molecular heterogeneity. Pediatr Transplant. 2004 Aug;8(4):344-8. Review.
   
   
5. Papez KE, Smoyer WE. Recent advances in congenital nephrotic syndrome. Curr Opin Pediatr. 2004 Apr;16(2):165-70. Review.
   
   
6. Gubler MC. Podocyte differentiation and hereditary proteinuria/nephrotic syndromes. J Am Soc Nephrol. 2003 Jun;14 Suppl 1:S22-6. Review.
   
   
7. Pollak MR. The genetic basis of FSGS and steroid-resistant nephrosis. Semin Nephrol. 2003 Mar;23(2):141-6. Review.

8. Regele HM, Fillipovic E, Langer B, Poczewki H, Kraxberger I, Bittner RE, Kerjaschki D. Glomerular expression of dystroglycans is reduced in minimal change nephrosis but not in focal segmental glomerulosclerosis. J Am Soc Nephrol. 2000 Mar;11(3):403-12.

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11. Weber S, Gribouval O, Esquivel EL, Moriniere V, Tete MJ, Legendre C, Niaudet P, Antignac C. NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. Kidney Int. 2004 Aug;66(2):571-9.
    
    
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15. Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodriguez-Perez JC, Allen PG, Beggs AH, Pollak MR. Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet. 2000 Mar;24(3):251-6.

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17. Barisoni L, Kriz W, Mundel P, D'Agati V. The dysregulated podocyte phenotype: a novel concept in the pathogenesis of collapsing idiopathic focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 1999 Jan;10(1):51-61.
    
    
18. Barisoni L, Bruggeman LA, Mundel P, D'Agati VD, Klotman PE. HIV-1 induces renal epithelial dedifferentiation in a transgenic model of HIV-associated nephropathy. Kidney Int. 2000 Jul;58(1):173-81.
    
    
19. Barisoni L, Kopp JB. Modulation of podocyte phenotype in collapsing glomerulopathies. Microsc Res Tech. 2002 May 15;57(4):254-62.
    
    
20. Moudgil A, Nast CC, Bagga A, Wei L, Nurmamet A, Cohen AH, Jordan SC, Toyoda M. Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy. Kidney Int. 2001 Jun;59(6):2126-33.

21. Bennett AN, Peterson P, Sangle S, Hangartner R, Abbs IC, Hughes GR, D'Cruz DP. Adult onset Still's disease and collapsing glomerulopathy: successful treatment with intravenous immunoglobulins and mycophenolate mofetil. Rheumatology (Oxford). 2004 Jun;43(6):795-9. Epub 2004 Mar 23.
    
    
22. Kumar S, Sheaff M, Yaqoob M. Collapsing glomerulopathy in adult still's disease. Am J Kidney Dis. 2004 May;43(5):e4-10.

23. Stein DF, Ahmed 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. 2001 Mar;46(3):530-5.

24. Shah S, Cavenagh J, Sheaf M, Thuraisingham RC. Remission of collapsing focal segmental glomerulosclerosis following chemotherapy for myeloma. Am J Kidney Dis. 2004 Feb;43(2):e10-2.
    
    
25. Bhowmik D, Dinda AK, Gupta S, Agarwal SK, Tiwari SC, Dash SC. Multiple myeloma presenting as collapsing glomerulopathy. Indian J Pathol Microbiol. 2003 Apr;46(2):233-4.

26. Markowitz GS, Appel GB, Fine PL, Fenves AZ, Loon NR, Jagannath S, Kuhn JA, Dratch AD, D'Agati VD. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol. 2001 Jun;12(6):1164-72.
    
    
27. Barri YM, Munshi NC, Sukumalchantra S, Abulezz SR, Bonsib SM, Wallach J, Walker PD. Podocyte injury associated glomerulopathies induced by pamidronate. Kidney Int. 2004 Feb;65(2):634-41.
    
    
28. Kunin M, Kopolovic J, Avigdor A, Holtzman EJ. Collapsing glomerulopathy induced by long-term treatment with standard-dose pamidronate in a myeloma patient. Nephrol Dial Transplant. 2004 Mar;19(3):723-6.