Podocytic Infolding Research Articles

Telitacicept as a novel treatment for refractory lupus nephritis complicated by podocytic infolding glomerulopathy

Telitacicept as a novel treatment for refractory lupus nephritis complicated by podocytic infolding glomerulopathy

A Case of Podocytic Infolding Glomerulopathy in an Allograft Kidney

Podocytic infolding glomerulopathy (PIG) is a rare disease diagnosed by its characteristic structure on electron microscopy. Histologically, there are microtubules and microspheres in the glomerular basement membrane (GBM). Most PIG has been reported in Japan, with a single case in South Korea; there are no previous reports of PIG in kidney transplant patients. Here, we report a 47-year-old Korean woman diagnosed with PIG after a kidney transplant. She was diagnosed with systemic lupus erythematosus. She was suspected of having lupus nephritis and subsequently underwent kidney transplantation. Routine testing showed increased proteinuria without renal functional impairment. A biopsy of the allograft kidney revealed mild interstitial fibrosis, tubular atrophy, and GBM thickening with intramembranous microspherules and microtubules on light microscopy. Electron microscopy showed GBM thickening with intramembranous microspherules and microtubules. These findings are consistent with PIG.

A Case of Podocytic Infolding Glomerulopathy with Diabetes Mellitus, Nephrotic Range Proteinuria and Positive Anti-PLA2R in Serum

A Case of Podocytic Infolding Glomerulopathy with Diabetes Mellitus, Nephrotic Range Proteinuria and Positive Anti-PLA2R in Serum

A case of Podocytic Infolding Glomerulopathy with SLE and literature review

BackgroundPodocytic infolding glomerulopathy (PIG) is a rare pathological change which was characterized by the microspheres or microtubular structures in the thickened glomerular basement membrane (GBM). Only a few dozen cases have been reported worldwide so far. Here we present a case of PIG with systemic lupus erythematosus.Case presentationA 61-year-old Chinese female was diagnosed with systemic lupus erythematosus with clinical manifestations of proteinuria, pleural effusion, seroperitoneum, anemia, leukopenia, thrombocytopenia, antinuclear antibody positive, and hypocomplementemia. She also had benign ovarian tumor and Epstein-Barr virus infection. Renal biopsy immunofluorescent staining showed IgM and C3 were granularly deposited along the capillary wall instead of typical “full house” features. Electron microscopy showed lots of microspheres structures were seen in the thickened GBM.ConclusionWe present a case of PIG in a patient with systemic lupus erythematosus. The mechanisms of PIG are unknown, but may be associated with connective tissue disease and podocyte injury.

Podocytic infolding in Schimke immuno-osseous dysplasia with novel SMARCAL1 mutations: a case report

BackgroundSchimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, progressive renal insufficiency and defective cellular immunity. Podocytic infolding glomerulopathy (PIG) is a newly proposed disease entity characterized by microspheres or microtubular structures associated with podocytes infolding into the glomerular basement membrane (GBM) on electron microscopy (EM).Case presentationA 4-year-old boy was admitted to our ward due to proteinuria and edema lasting 1 month. He had a short trunk and demonstrated subtle dysmorphology, with a triangular shape, a broad nasal bridge and a bulbous nasal tip. The laboratory findings were as follows: lymphocytes, 0.5 × 109/L; urine protein, 3.67 g/d; albumin, 9.8 g/L; and cholesterol, 11.72 mmol/L. Skeletal X rays showed small iliac wings, small ossification centers of the capital femoral epiphyses, shallow dysplastic acetabular fossae and mildly flattened vertebrae. The specimen for light microscopy (LM) suggested focal segmental glomerulosclerosis (FSGS). EM revealed a focal thickness of the GBM with some cytoplasmic processes of podocyte infolding into the GBM. Gene sequencing showed novel compound heterozygous mutations in the SMARCAL1 gene (c.2141 + 5G > A; c.2528 + 1G > A) that were inherited from his parents. Finally, we established the diagnosis of SIOD and treated him with diuretics and angiotensin-converting enzyme inhibitors (ACEIs).ConclusionThe pathogenic mechanism of PIG has not been clarified. Further studies are required to understand whether gene mutations, especially those related to podocytes, contribute to the pathogenesis of podocytic infolding.

Post-Transplant Membranous Nephropathy Associated with Chronic Active Antibody-Mediated Rejection and Hepatitis C Infection after Deceased Donor Renal Transplantation

A 53-year-old woman who had undergone deceased donor kidney transplantation twice, at 35 and 43 years of age, presented with renal impairment. She was infected with hepatitis C virus (HCV). The histology of the graft kidney revealed post-transplant membranous nephropathy (MN) with podocytic infolding and antibody-mediated rejection (AMR). IgG subclass staining showed fine granular deposits of IgG1 and IgG3, but not IgG4, in the glomerular capillary walls. Panel reactive antibody scores for human leukocyte antigen class I and class II were 92.67% and 66.68%, respectively. Thus, this case of post-transplanted MN was considered to be associated with AMR and HCV infection.

A case of podocytic infolding glomerulopathy with multiple myeloma

BackgroundPodocytic infolding glomerulopathy (PIG) is a recently described condition causing rare pathological changes to the glomeruli, and has attracted considerable attention. PIG is characterized by specific changes to the thickened glomerular basement membrane (GBM), including microspheres, microtubular structures, and podocytic infolding. Only a small number of cases of PIG have been reported. The clinical features and pathogenesis of this condition are still unclear. To elucidate the characteristics of this glomerulopathy, it is necessary to accumulate information from reported cases. We present here the first reported case of PIG with multiple myeloma.Case presentationA 79-year-old Japanese man was admitted to his local hospital with proteinuria, hypergammaglobulinemia, hypoalbuminemia, and kidney dysfunction. Laboratory tests revealed monoclonal IgG(λ) M proteins in the serum and Bence-Jones proteins in the urine. Bone marrow aspiration showed monoclonal plasma cell proliferation, indicating a diagnosis of multiple myeloma. Renal biopsy was performed to determine the cause of the proteinuria and kidney dysfunction. Histological examination of the biopsy specimen showed glomeruli with an irregularly thickened GBM and bubble-like structures in the capillary walls. Immunofluorescence staining did not show glomerular deposition of immunoglobulins, light chains, or complement components. Congo red staining did not show amyloid deposition. Electron microscopy showed an irregularly thickened GBM with unusual structures in the glomerular capillary walls including podocytic infolding and microspheres, suggesting PIG. There were no electron-dense deposits in the GBM, while various findings indicating podocyte injury were detected.ConclusionWe present here the first reported case of PIG in a patient with multiple myeloma. The mechanisms underlying the development of PIG in multiple myeloma are unknown, but may be associated with podocyte injury.

A case of a new disease entity: podocytic infolding glomerulopathy

A 41-year-old woman was discovered to have enteric infection of Aeromonas caviae and was treated with antibiotics. Subsequently she developed nephrotic syndrome. Renal biopsy showed a non-argentaffine hole in the glomerular basement membrane (GBM) in PAM stain with IgG and C3 deposition. This finding was similar to membranous glomerulonephritis. However, electron microscopy showed no electron dense deposits but microspheres or microtubular structures associated with podocytic infolding into the GBM. Corticosteroid treatment resulted in rapid remission. 1 This case corresponds to a new disease entity of podocytic infolding glomerulopathy, which was proposed by a working group of The Japanese Society of Nephrology on the basis of 25 cases corrected from 17 institutions all over Japan. 2 The question arises whether these morphological changes are specific for a new disease entity or they could reflect a nonspecific cellular response of the podocyte to an injury.

足細胞陥入糸球体症国内調査ワーキンググループ (WG) 委員会報告

足細胞陥入糸球体症国内調査ワーキンググループ (WG) 委員会報告

Invagination and infolding of podocytes in glomerular basement membrane in the cases of primary membranous nephropathy

The ultrastructural findings of membranous nephropathy (MN) are well described. Recently, podocyte infolding in the glomerular basement membrane (GBM) has been observed to be a unique ultrastructural finding formed from diffuse spherical microparticles and microtubules in the GBM. However, these alterations of glomerular epithelial cells have not been well characterized in MN. We selected 126 renal biopsies of primary MN that were diagnosed by light microscopy and immunofluorescence. In these biopsies, we investigated the ultrastructural alterations of GBM and podocytes, especially the presence of podocyte invagination, podocyte infolding, and spherical microparticles in the GBM. In 98 cases (77.8%) we ultrastructurally detected occasional invagination of podocytes in the GBM within or around electron-dense or lucent deposits in mainly stage II-III of MN. In 40 cases (31.7%), we found spherical microparticles in addition to the podocyte invaginations in the GBM. In our cases, spherical microparticles were divided into three types; podocyte infolding, cell debris and virus-like particle types. Only one case displayed numerous spherical microparticles (microspheres) that were probably caused by infolding of podocytes. These microspheres, about 80 nm in diameter, were covered by unit membrane, and were accompanied by similar-sized microtubules and protrusions of podocytes. The spherical microparticles in the other cases were associated with cell debris (n = 23) or virus-like particles (n = 16) and were not connected with podocytes. Podocyte invagination associated with subepithelial deposits was a common pathological finding of primary MN, especially stage II-III of MN. The spherical microparticles in GBM in the case of MN may be associated with not only podocyte infolding but also cell debris and virus-like particles. The spherical microparticles in GBM due to diffuse podocyte infolding was considered as a new pathology finding of the GBM and may appear to be a new glomerular disease entity termed podocytic infolding glomerulopathy.

Analysis of intra-GBM microstructures in a SLE case with glomerulopathy associated with podocytic infolding

Systemically podocytic infolding into the GBM which causes nonargyrophilic holes in the GBM in association with intra-GBM microstructures has been considered as a new pathological entity. However, its pathomechanisms are largely unknown. We analyzed intra-GBM microstructures in an SLE patient with glomerulopathy associated with podocytic infolding by immunoelectron microscopy for vimentin (a marker for both podocyte and endothelium) and C5b-9 and by 3D reconstruction of transmission electron microscopy (TEM) images by computer tomography method. Immunofluorescent study showed immunoglobulin deposition in a diffuse, capillary pattern; however, electron-dense deposits like stage 3 membranous nephropathy could be found only in some capillary loops by TEM in spite of the systemic existence of podocytic infolding and the intra-GBM microstructures. Three-dimensional reconstructed images of the TEM images revealed that some of the intra-GBM microstructures made connections with the podocyte. The clustered microstructures underneath the podocyte and their surroundings looked as a whole like the degraded part of podocyte in 3D reconstructed images. Immunoelectron microscopy showed that vimentin was positive in most intra-GBM microstructures. C5b-9 was positive along the entire epithelial side of the GBM and in some microstructures, suggesting that the podocytes may be attacked by C5b-9 and that the microstructures may contain C5b-9 bound cellular membranes. Intra-GBM microstructures may be originated mainly from the podocyte. Podotyte and GBM injuries caused by C5b-9 attack to podocytes might contribute in part to podocytic infolding and intra-GBM microstructures in this case.

Proposal of podocytic infolding glomerulopathy as a new disease entity: a review of 25 cases from nationwide research in Japan

A rare and peculiar glomerulopathy has begun to be recognized in Japan. The Japanese Society of Nephrology has established a research working group and has collected cases from all over Japan in an attempt to understand the complete spectrum of this glomerulopathy. The diagnostic criterion, which was needed to collect the cases, was proposed as a glomerulopathy showing microspheres or microtubular structures or both associated with podocytic infolding into the glomerular basement membrane (GBM) on electron microscopy. The lesion shows a non-argentaffin hole in the GBM with periodic acid methenamine silver staining and is similar to membranous glomerulonephritis. Twenty-five cases were collected from 17 institutions. Patients were 20-69 years old (19 women, 6 men). Seventeen patients also had collagen diseases such as lupus nephritis and Sjögren's syndrome. All patients had proteinuria. Proteinuria showed a remission in 15 of 23 patients within 12 months, but proteinuria remained higher than 1.0 g/day in five patients despite different types of therapy. Podocytic infolding including microspheres showed either positive or negative staining for immunoglobulins. Cluster formation of microspheres was found in 4 of 17 patients with collagen disease, and in five out eight patients without collagen disease. Electron-dense deposits in the GBM were also found in 6 of 17 patients with collagen disease but were not found in eight patients without collagen disease. Some patients might have a subtype of lupus nephritis, class V, or membranous glomerulonephritis. However, we propose a new disease entity, podocytic infolding glomerulopathy, as a common basis of all 25 patients, because we suspect that microspheres or microtubular structures or both can be derived from podocytic infolding.

Unique microstructures and podocytic infolding in glomerular basement membrane associated with collagen diseases: a report of three cases

Unique renal histopathological appearances, consisting of podocytic infolding and microstructures in the glomerular basement membrane (GBM) were identified in the renal biopsies from three patients with collagen diseases such as systemic lupus erythematosus (lupus nephritis, class II) and Sjögren's syndrome. In each case, the GBM contained microstructures, including microspheres and microtubular structures, accompanied by podocytic infolding into the GBM when examined by electron microscope. The size of the microstructures in the GBM ranged from 40 to 160 nm. Glomerular endothelial cells also seemed to be infolded in the GBM in a case with lupus nephritis. The response to glucocorticoid therapy was favorable in two cases. The cause of these morphological changes in the GBM might be associated with autoimmune disorders.

Unusual glomerulopathy with aggregated subepithelial microspheric particles resembling membranous nephropathy: a variant of glomerulopathy associated with podocytic infolding?

A 69-year-old woman presented with unusual electron microscopic findings. The patient was admitted to ascertain the cause of her persistent proteinuria, and kidney biopsy was performed. While light microscopic findings and immunofluorescence study suggested membranous nephropathy, electron microscopic study showed microspheric particles aggregated in the subepithelial space where electron-dense deposits should have existed. While the microspheric particles could have been unusual and rough deposits, detailed study suggested that the particles could be parts of glomerular podocytes, for example foot processes. This unusual finding was considered as being in a unique clinical course of membranous nephropathy, but a variant of glomerulopathy associated with podocytic infolding, proposed by Joh et al. (J Nephrol 49:61-67, 2007), could not be excluded.

A case of lupus nephritis coexisting with podocytic infolding associated with Takayasu’s arteritis

A 61-year-old Japanese woman with both Takayasu's arteritis (TA) and systemic lupus erythematosus (SLE) presented with proteinuria due to glomerulopathy associated with podocytic infolding. She presented with unequal pulses in the upper extremities at 38 years old. TA was diagnosed on the basis of angiographic identification of stenosis in the left subclavian artery. Eight years after onset of TA, SLE was diagnosed on the basis of clinical and laboratory findings, including proteinuria, hematological and immunological abnormalities, high titer of antinuclear antibody, and a positive lupus band test on the skin. A renal biopsy showed lupus nephritis coexisting with podocytic infolding associated with TA, which has rarely been reported. After low-dose prednisolone therapy and immunosuppressive therapy by cyclosporine for 14 years, proteinuria has persisted without deterioration of serum creatinine levels.

A case report of glomerulopathy-associated podocytic infolding in a patient with tumor lysis syndrome

A 59-year-old man underwent total gastrectomy and splenectomy for gastric cancer 14 months before admission. The pathological diagnosis was neuroendocrine carcinoma of the stomach. Eight months after the operation, systemic chemotherapy with irinotecan and cisplatin was started because of multiple metastases to lymph nodes. After two courses of chemotherapy, renal function continued to decline. Renal biopsy showed acute tubular necrosis with cast formation, where needle crystallization was found. These clinicopathological findings suggested that tumor lysis syndrome was the cause of acute renal insufficiency. Moreover, diffuse, global bubbling and focal segmental spike formation were revealed by periodic acid-silver methenamine stain in the glomerular basement membrane. Electron microscopy showed an infolding of the cytoplasm of podocytes into the basal basement membrane and spotty electron-lucent areas. These ultrastructural findings, but not epimembranous deposits, corresponded with the bubbling on PAM staining. The present case was a rare case of glomerulopathy associated with podocytic infolding, which was not associated with collagen disease but with tumor lysis syndrome.

A case of lupus nephritis with diffuse podocytic infolding into the glomerular basement membrane

In this manuscript, we describe a case of lupus nephritis with diffuse podocytic infolding in the glomerular basement membrane (GBM). A 23-year-old woman presenting with proteinuria, leukopenia, a high value of antinuclear antibody, and positive for anti-dsDNA and anti-Sm antibodies was diagnosed with systemic lupus erythematosus. A renal biopsy was performed which showed diffuse change in the GBM and focal segmental mesangial hypercellularity under light microscopy. The GBM showed diffuse mild thickening and diffuse irregular stippling (bubble-like appearance) on staining with periodic acid-silver methenamine. However, spike formation was only occasionally seen. An immunofluorescence study was conducted which revealed fine granular deposition of IgG (2+) along the glomerular capillary walls; however, granular deposits of C1q (1+) and C3 (1+) were primarily detected in the mesangial areas. Diffuse irregular GBM thickening with dispersed distribution of microspheres and microtubules was observed using electron microscopy. In addition, these structures were chiefly detected on the epithelial side of the GBM. Since these structures seemed to connect to podocytes, we believed that the formation of these microspheres and microtubules is caused by the infolding of podocytes. This case shows a unique pathological finding, and may belong to a new glomerular disease entity characterized by podocytic infolding. After a renal biopsy, the patient received oral prednisolone 0.8 mg/kg day initially, and her complete remission status continued for 5 years.

Proposal of podocytic infolding glomerulopathy as a new disease entity

In recent case presentations at conferences in Japan and in personal consultations, we had begun to recognize a rare and peculiar glomerulopathy, in which microspheres and microtubular structures are shown in the glomerular basement membrane (GBM) in association with infolding of cytoplasmic processes of podocytes into the GBM. This rare and peculiar glomerulopathy has not yet been included in the World Health Organization’s classification of glomerular diseases, and only a few case reports have been published in the literature. We had no idea whether this lesion indicated a new disease entity or a transient morphological finding of a well-known disease. It was necessary to discern a clearer clinical and pathological profile and an effective treatment. However, it was difficult to accumulate cases at a single institution, because this glomerulopathy is extremely rare. Therefore, the Japanese Society of Nephrology has established a research working group and has collected cases from all over Japan in an attempt to understand the complete spectrum of this glomerulopathy.

Are the cytoplasmic microstructures within GBM pathologically significant?

The current issue of CEN features the so-called podocytic infolding glomerulopathy, which is characterized by the emergence of spherical or tubular cytoplasmic microstructures in association with cytoplasmic projections of podocytes within the thickened glomerular basement membrane (GBM) in electron micrographs as well as nonargyrophilic holes in the GBM at light microscopic levels [1]. This type of glomerular change has been recently proposed as a possible new pathological entity in Japan. The three original articles and 15 case reports in this issue are the first survey of the cases with this type of glomerular pathology. The GBM and other basement membranes are made up by self-assembly of constituent molecules, such as collagen type IV and laminin, which are secreted by the adjacent parenchymal cells. The established basement membranes are thought to be a stable structure, providing a mechanical support and constant milieu for the parenchymal cells. Reflecting the structural and functional stability of basement membranes, cytoplasmic microstructures and cellular projections have been only rarely reported within the basement membranes. One of those rare observations includes the basement membranes of the proximal convoluted tubule, which contains occasional cytoplasmic vesicles at the concavity of the tubular bend [2]. These vesicles are thought to be torn off from the basal cytoplasm of the proximal tubular cells due to higher mechanical stress at this location, and preserved within the basement membranes which shield the vesicles from disposal by interstitial cells. In this issue, Fujigaki et al. [3] showed clearly that the microstructures in the GBM are connected with the cellular processes of podocytes by three dimensional analysis. Another example of heterogeneity of the basement membrane was found around the ductal epithelium of excretory glands, including the liver, pancreas, lacrimal glands and salivary glands [4, 5], where the cellular projections of ductal epithelial cells were associated multilaminar basement membranes and fine collagen fibrils. The multilaminar lamina densa together with fine collagen fibrils were thought to be produced by the epithelial cells. The functional significance of cellular projection of ductal epithelial cells are unknown, but may be correlated the extremely high mechanical demand of this epithelium. The 25 cases reported in this issue revealed clearly that the podocyte infolding glomerulopathy represents not solitary unreproducible observations, but constantly reproducible ones, although the incidence is extremely low. The unique microscopic appearance suggests the common pathological process of these cases, but the etiology is obviously diverse. In this issue, Masuda et al. [6] reported a different type of glomerulopathy with cytoplasmic microstructures within GBM, and suggested that they represented cellular debris trapped during the remodeling of the GBM. What does the morphology of podocyte infolding glomerulopathy indicate? It would be to some extent rationalized to suppose that the podocytes in this condition are surrendered to more mechanical demand to produce more GBM materials and make basal projections which are torn off to deliver cytoplasmic microstructures to be remained for considerable period in GBM. The paucity of the cases and the diversity of the etiology at present prevent further analysis of the pathology. T. Sakai (&) Department of Anatomy and Life Structure, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan e-mail: tatsuo@juntendo.ac.jp

Lupus nephritis with podocytic infolding and intramembranous microstructures

We describe a 24-year-old woman with a distinctive glomerular lesion. She presented with nephrotic syndrome and the diagnosis of systemic lupus erythematosus was made on the basis of laboratory and clinical findings. Renal biopsy showed a bubbling appearance of the glomerular capillary wall indicating lupus nephritis class V. On an electron microscopy, the glomerular basement membrane (GBM) was irregularly thickened and contained abundant vesicular and microtubular bodies. In addition, there were many epithelial foot processes infolding into the GBM. A few small deposits were observed beneath the foot processes and around the vesicular and microtubular bodies. Although the clinicopathological significance of podocytic infolding has not been fully elucidated, it may be a novel morphological entity in the glomerulonephritides.