| 1. |
- Demetris, A J, et al.
(author)
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2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection.
- 2016
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In: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. - : Elsevier BV. - 1600-6143. ; 16:10, s. 2816-2835
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Journal article (peer-reviewed)abstract
- The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.
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| 2. |
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| 3. |
- Levin, A., et al.
(author)
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Novel insights into the disease transcriptome of human diabetic glomeruli and tubulointerstitium
- 2020
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In: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 35:12, s. 2059-2072
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Journal article (peer-reviewed)abstract
- Background. Diabetic nephropathy (DN) is the most common cause of end-stage renal disease, affecting similar to 30% of the rapidly growing diabetic population, and strongly associated with cardiovascular risk. Despite this, the molecular mechanisms of disease remain unknown. Methods. RNA sequencing (RNAseq) was performed on paired, micro-dissected glomerular and tubulointerstitial tissue from patients diagnosed with DN [n = 19, 15 males, median (range) age: 61 (30-85) years, chronic kidney disease stages 1-4] and living kidney donors [n = 20, 12 males, median (range) age: 56 (30-70) years]. Results. Principal component analysis showed a clear separation between glomeruli and tubulointerstitium transcriptomes. Differential expression analysis identified 1550 and 4530 differentially expressed genes, respectively (adjusted P < 0.01). Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses highlighted activation of inflammation and extracellular matrix (ECM) organization pathways in glomeruli, and immune and apoptosis pathways in tubulointerstitium of DN patients. Specific gene modules were associated with renal function in weighted gene co-expression network analysis. Increased messengerRNA (mRNA) expression of renal damage markers lipocalin 2 (LCN) and hepatitis A virus cellular receptor1 (HAVCR1) in the tubulointerstitial fraction was observed alongside higher urinary concentrations of the corresponding proteins neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in DN patients. Conclusions. Here we present the first RNAseq experiment performed on paired glomerular and tubulointerstitial samples from DN patients. We show that prominent disease-specific changes occur in both compartments, including relevant cellular processes such as reorganization of ECM and inflammation (glomeruli) as well as apoptosis (tubulointerstitium). The results emphasize the potential of utilizing high-throughput transcriptomics to decipher disease pathways and treatment targets in this high-risk patient population.
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| 5. |
- Levin, A., et al.
(author)
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The role of dendrin in IgA nephropathy
- 2023
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In: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 38:2, s. 311-321
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Journal article (peer-reviewed)abstract
- Background Immunoglobulin A nephropathy (IgAN) and its systemic variant IgA vasculitis (IgAV) damage the glomeruli, resulting in proteinuria, hematuria and kidney impairment. Dendrin is a podocyte-specific protein suggested to be involved in the pathogenesis of IgAN. Upon cell injury, dendrin translocates from the slit diaphragm to the nucleus, where it is suggested to induce apoptosis and cytoskeletal changes, resulting in proteinuria and accelerated disease progression in mice. Here we investigated gene and protein expression of dendrin in relation to clinical and histopathological findings to further elucidate its role in IgAN/IgAV. Methods Glomerular gene expression was measured using microarray on 30 IgAN/IgAV patients, 5 patients with membranous nephropathy (MN) and 20 deceased kidney donors. Dendrin was spatially evaluated on kidney tissue sections by immunofluorescence (IF) staining (IgAN patients, n = 4; nephrectomized kidneys, n = 3) and semi-quantified by immunogold electron microscopy (IgAN/IgAV patients, n = 21; MN, n = 5; living kidney donors, n = 6). Histopathological grading was performed according to the Oxford and Banff classifications. Clinical data were collected at the time of biopsy and follow-up. Results Dendrin mRNA levels were higher (P = .01) in IgAN patients compared with MN patients and controls and most prominently in patients with preserved kidney function and fewer chronic histopathological changes. Whereas IF staining did not differ between groups, immunoelectron microscopy revealed that a higher relative nuclear dendrin concentration in IgAN patients was associated with a slower annual progression rate and milder histopathological changes. Conclusion Dendrin messenger RNA levels and relative nuclear protein concentrations are increased and associated with a more benign phenotype and progression in IgAN/IgAV patients.
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| 11. |
- Dahlgren, Lars-Ove, et al.
(author)
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To be and to have a critical friend in medical teaching
- 2006
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In: Medical Education. - : Wiley. - 0308-0110 .- 1365-2923. ; 40:1, s. 72-78
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Journal article (peer-reviewed)abstract
- BACKGROUND In order to stimulate reflection and continuous professional development, a model of critical friends evaluating each other was introduced in medical education. OBJECTIVE To investigate whether the critical friend concept can serve as a pragmatic model for evaluation of medical teachers and as a fruitful tool for enhancing self-knowledge and professional development among medical educators. METHODS Three pairs of critical friends were formed, consisting of experienced medical teachers (n = 6) at the Karolinska Institutet. Each teacher was assigned to give 1 lecture and 1 seminar in his or her specific research or clinical field. The critical friend evaluated the performance in class, acting as an observer using a pre-formed protocol. The evaluation was communicated to the teacher during a 45-minute session within 48 hours after the teaching session. Each of the 6 teachers was criticised and gave criticism within the pair configurance. The outcome of the process was evaluated by an experimenter, not participating in the process, who performed a semistructured interview with each of the 6 teachers. RESULTS Each teacher had a different way of reflecting on teaching after the project than before and made changes in his or her way of teaching. We also noted that being a critical friend may be even more effective than having one. The majority of the feedback provided was positive and valuable. CONCLUSION To be and to have a critical friend is worth the extra workload. Therefore, the critical friend concept should be made part of regular teaching practice.
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| 16. |
- Sorenby, A, et al.
(author)
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Improved histological evaluation of vascularity around an immunoisolation device by correlating number of vascular profiles to glucose exchange
- 2004
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In: Cell transplantation. - : SAGE Publications. - 0963-6897 .- 1555-3892. ; 13:6, s. 713-719
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Journal article (peer-reviewed)abstract
- The aim of this study was to determine which vessels are important for the exchange of small molecules, such as glucose, from the microcirculation into an immunoisolation device. Reasonably, those vessels should be the ones of interest in histological evaluations. In a previous study, we examined the diffusion of glucose from the microcirculation into immunoisolation devices that had been implanted subcutaneously in rats for various times (i.e., 1, 2, and 4 weeks and 3 months). The glucose kinetic data were then correlated with the number of vascular profiles within 15 and 250 μm from the device. Significant correlations were found only at 250 μm. To examine the relation further between function and vascularization, we used the histological samples from the previous study and counted vascular profiles within various distances between 15 and 400 μm from the device. The number was then correlated with the already available glucose kinetic data. The highest correlations were found at 75 and 100 μm (p < 0.05). We therefore suggest that vascular profiles within 100 μm should be used when evaluating the vascularity of tissue surrounding an immunoisolation device. We also studied neovascularization asymmetries between the side of the membrane facing the skin and that facing the muscle. At 1 and 2 weeks about half of the devices were mainly vascularized on the side facing the skin, whereas the rest were equally vascularized on the two sides. At 3 months, all devices were well vascularized, and no striking vascularization asymmetries were seen.
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| 23. |
- Genberg, H, et al.
(author)
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Pharmacodynamics of rituximab in kidney allotransplantation
- 2006
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In: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. - : Elsevier BV. - 1600-6135. ; 6:10, s. 2418-2428
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Journal article (peer-reviewed)
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| 24. |
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| 27. |
- Krmar, R T, et al.
(author)
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Acute renal failure in dense deposit disease: complete recovery after combination therapy with immunosuppressant and plasma exchange.
- 2011
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In: Clinical Nephrology. - 0301-0430. ; 75:S1, s. 4-10
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Journal article (peer-reviewed)abstract
- We describe the clinical course of a female adolescent who was followed because of isolated microhematuria and hypocomplementemia before admission to hospital with a sudden onset of acute renal failure. At presentation, she exhibited complement consumption through the complement alternative pathway (AP) while other serologic tests were negative. Renal biopsy revealed dense deposit disease (DDD) with a crescentic pattern. Intravenous methylprednisolone, followed by plasma exchange (PE), and intravenous cyclophosphamide pulses were started shortly after admission. C3NeF and anti-factor H antibody tests were negative. Serum factor H and I levels were normal as well as factor H activity. Screening for mutation in the factor H gene revealed the H402 allele variant. Clinical remission, defined as normalization in renal function and in the activity levels of the complement AP, was noted at one month post-presentation and throughout the follow-up. A repeat renal biopsy showed the disappearance of crescent formation, whereas electron microscopy revealed no regression in dense transformation of the lamina densa. In summary, our patient was successfully treated with immunosuppressant and PE. The absence of known factors associated with DDD suggests that, in this particular case, other regulatory mechanisms of complement AP might have been involved in the disease process.
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| 28. |
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| 30. |
- Magne, J., et al.
(author)
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The minor allele of the missense polymorphism Ser251Pro in perilipin 2 (PLIN2) disrupts an alpha-helix, affects lipolysis, and is associated with reduced plasma triglyceride concentration in humans
- 2013
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In: Faseb Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 27:8, s. 3090-3099
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Journal article (peer-reviewed)abstract
- Perilipin 2 (PLIN2) is the most abundant lipid droplet (LD)-associated protein in nonadipose tissue, and its expression correlates with intracellular lipid accumulation. Here we identified a missense polymorphism, Ser251Pro, that has major effect on protein structure and function, along with an influence on human plasma triglyceride concentration. The evolutionarily conserved Ser251Pro polymorphism was identified with the ClustalW program. Structure modeling using 3D-JigSaw and the Chimera package revealed that the Pro251 allele disrupts a predicted -helix in PLIN2. Analyses of macrophages from individuals carrying Ser251Pro variants and human embryonic kidney 293 (HEK293) cells stably transfected with either of the alleles demonstrated that the Pro251 variant causes increased lipid accumulation and decreased lipolysis. Analysis of LD size distribution in stably transfected cells showed that the minor Pro251 allele resulted in an increased number of small LDs per cell and increased perilipin 3 protein expression levels as compared with cells carrying the major Ser251 allele. Genotyping of 2113 individuals indicated that the Pro251 variant is associated with decreased plasma triglyceride and very low-density lipoprotein concentrations. Altogether, these data provide the first evidence of a polymorphism in PLIN2 that affects PLIN2 function and may influence the development of metabolic and cardiovascular diseases.
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| 31. |
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| 33. |
- Rafael, E, et al.
(author)
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Improved survival of macroencapsulated islets of Langerhans by preimplantation of the immunoisolating device: a morphometric study
- 2003
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In: Cell transplantation. - : SAGE Publications. - 0963-6897 .- 1555-3892. ; 12:4, s. 407-412
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Journal article (peer-reviewed)abstract
- Encapsulation of cells in a semipermeable membrane may in the future provide an opportunity to treat a variety of endocrine and neurological disorders, without the need for lifelong immunosuppression. The physiological conditions in the device are crucial factors for graft survival. Previously, we have shown that the exchange across the immunoisolating membrane and the microcirculation around the TheraCyte™ device increase around 3 months after implantation. The aim of this study was to determine whether preimplantation of the TheraCyte™ device would improve the survival of a later transplanted islet graft. A TheraCyte™ device was implanted SC on one side of the back of a nondiabetic SD rat. After 3 months, 1500 islets isolated from SD rats were transplanted via the device port. At the same time, another device, loaded with the same number of islets, was implanted on the other side of the back. Both devices were explanted 2 weeks after islet transplantation (i.e., 3.5 months and 0.5 month after device implantation, respectively). Six pairs of devices were evaluated by morphometery. The volume densities of viable islets were 0.22 ± 0.04 in the preimplanted device vs. 0.06 ± 0.03 in the nonpreimplanted one (p < 0.05). The corresponding volume densities of fibrosis and necrosis were 0.64 ± 0.13 vs. 0.85 ± 0.08 (p < 0.05) and 0.11 ± 0.14 vs. 0.09 ± 0.07 (ns), respectively. When the absolute volumes (mm3) were calculated, preimplanted devices contained 1.1 ± 0.7 endocrine cells while nonpreimplanted ones contained 0.4 ± 0.2 (p < 0.05). The percentages of insulin-positive β-cells in the preimplanted versus nonpreimplanted device were 80 ± 5% and 67 ± 6%, respectively (p < 0.01). The corresponding volumes of fibrotic tissue were 3.0 ±1.8 vs. 5.2 ± 1.2 (p < 0.05), while the amount of necrotic tissue did not differ significantly (0.42 ± 0.5 vs. 0.50 ± 0.3). Preimplantation of the TheraCyte™ device seems to improve the survival of an encapsulated islet graft and reduce fibroblast outgrowth in the device.
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| 34. |
- Rafael, E, et al.
(author)
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In vivo evaluation of glucose permeability of an immunoisolation device intended for islet transplantation: a novel application of the microdialysis technique
- 1999
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In: Cell transplantation. - : SAGE Publications. - 0963-6897 .- 1555-3892. ; 8:3, s. 317-326
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Journal article (peer-reviewed)abstract
- Immunoisolation devices consist of semipermeable membranes chosen to protect the islets from the immune system but still allow sufficient passage of nutrients, oxygen, and the therapeutic products, insulin. The exchange between the device and the microcirculation will influence the survival of the graft as well as the metabolic efficacy of the islet implant. Glucose is the important trigger factor for insulin secretion. In this study, we evaluate the in vivo glucose permeability of the Theracyte™ immunoisolation device at various times after implantation. Empty devices were implanted SC in rats. The glucose kinetics in the device was compared to that in the SC tissue during IV glucose tolerance tests (IVGTTs), using the microdialysis technique. In rats studied on day 1, or 1, 2, and 4 weeks after implantation, the peak glucose levels (Cmax) were significantly lower, the times-to-peak (TTP) were significantly longer, and the areas under the curve during the first 40 min (AUC0–40) were significantly smaller in the device than in the SC fat. However, at 3 months all parameters improved and Cmax, TTP, and AUC0–40 in the device did not differ significantly from those measured in the SC fat. Thus, during the first 4 weeks the device constitutes a significant diffusion barrier, but at 3 months the exchange between the lumen of devices and the blood stream improves. Our data indicate that implantation of the device several months before transplantation of the cellular graft would improve the exchange across the membrane during the early posttransplant period. This should have positive effects on graft survival and function. We also suggest that microdialysis is a useful tool for evaluating the in vivo performance of macroencapsulation devices.
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| 35. |
- Rafael, E, et al.
(author)
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In vivo studies on insulin permeability of an immunoisolation device intended for islet transplantation using the microdialysis technique
- 1999
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In: European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes. - : S. Karger AG. - 0014-312X. ; 31:3, s. 249-258
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Journal article (peer-reviewed)abstract
- In this study, insulin was injected into Theracyte<sup>TM</sup> immunoisolation devices to analyze changes in the permeability of the device over time after implantation. The recovery of insulin was studied after subcutaneous implantation of the devices in rats, using the microdialysis technique. The area under the insulin cocnetration vs. time curves (AUC) after insulin injection in devices implanted 1 day previously did not differ significantly from the AUC after subcutaneous injection. At 1, 2 and 4 weeks after implantation, the recovery of insulin was significantly reduced, but at 3 months, the AUC was not significantly different from that in the control group. Histological examination showed that the number of vascular profiles within 15 μm of the device were significantly higher at 2, 4 weeks and 3 months after transplantation when compared to numbers at 1 week. The design of the device allows transplantation of cells at a chosen time point after its implantation. Delayed filling of the device would allow neovascularization of the device surface before graft implanatation and we suggest that such a schedule might improve function of the encapsulated graft.
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| 36. |
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| 37. |
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| 38. |
- Sasai, F, et al.
(author)
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Inhaled silica nanoparticles cause chronic kidney disease in rats
- 2022
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In: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 323:1, s. F48-F58
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Journal article (peer-reviewed)abstract
- Inhalation of silica nanoparticles (SiNPs) released during the burning of sugarcane has been postulated to have a role in chronic kidney disease of unknown etiology (CKDu). We administered 200- and 300-nm amorphous SiNPs to rats by aspiration and observed kidney damage with tubular injury and inflammation that persisted even after stopping the SiNP exposure. These findings support the hypothesis that human exposure to SiNPs found in sugarcane ash could have a participatory role CKDu.
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| 39. |
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| 40. |
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| 41. |
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| 42. |
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| 43. |
- Zambrano, S., et al.
(author)
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GPRC5b Modulates Inflammatory Response in Glomerular Diseases via NF-kappa B Pathway
- 2019
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In: Journal of the American Society of Nephrology. - : Ovid Technologies (Wolters Kluwer Health). - 1046-6673 .- 1533-3450. ; 30:9, s. 1573-1586
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Journal article (peer-reviewed)abstract
- Background Inflammatory processes play an important role in the pathogenesis of glomerulopathies. Finding novel ways to suppress glomerular inflammation may offer a new way to stop disease progression. However, the molecular mechanisms that initiate and drive inflammation in the glomerulus are still poorly understood. Methods We performed large-scale gene expression profiling of glomerulus-associated G protein-coupled receptors (GPCRs) to identify new potential therapeutic targets for glomerulopathies. The expression of Gprc5b in disease was analyzed using quantitative PCR and immunofluorescence, and by analyzing published microarray data sets. In vivo studies were carried out in a podocyte-specific Gprc5b knockout mouse line. Mechanistic studies were performed in cultured human podocytes. Results We identified an orphan GPCR, Gprc5b, as a novel gene highly enriched in podocytes that was significantly upregulated in common human glomerulopathies, including diabetic nephropathy, IgA nephropathy, and lupus nephritis. Similar upregulation of Gprc5b was detected in LPS-induced nephropathy in mice. Studies in podocyte-specific Gprc5b knockout mice showed that Gprc5b was not essential for normal development of the glomerular filtration barrier. However, knockout mice were partially protected from LPS-induced proteinuria and recruitment of inflammatory cells. Mechanistically, RNA sequencing in Gprc5b knockouts mice and experiments in cultured human podocytes showed that Gpr5cb regulated inflammatory response in podocytes via NF-kappa B signaling. Conclusions GPRC5b is a novel podocyte-specific receptor that regulates inflammatory response in the glomerulus by modulating the NF-kappa B signaling pathway. Upregulation of Gprc5b in human glomerulopathies suggests that it may play a role in their pathogenesis.
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| 44. |
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| 46. |
- Ackefors, M., et al.
(author)
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Peg-IFN and ribavirin treatment for recurrence of genotype 2 and 3 hepatitis C after liver transplantation
- 2015
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In: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 0036-5548 .- 1651-1980. ; 47:4, s. 209-217
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Journal article (peer-reviewed)abstract
- Background: Relapse of hepatitis C virus (HCV) infection after liver transplantation (LT) is universal. Tolerance for treatment with pegylated-interferon (peg-IFN) and ribavirin (RBV) is suboptimal and withdrawals due to adverse events frequent. We sought to improve tolerance for treatment to improve outcome. Methods: We used concentration-guided RBV dosing to achieve an intended 10 mu mol/L concentration with darbepoetin support in combination with peg-IFN alfa-2a, 180 mu g for genotype 1 and 135 mu g for genotype 2/3 to improve tolerance. Results: A total of 51/54 patients (94%) completed a full treatment course. In the per-protocol analysis 43% of patients (22/51) achieved sustained virological response (SVR), 82% with HCV genotype 2/3 and 22% with genotype 1, p = 0.0001. Patients with IL28B CC achieved SVR in 73% (8/11) and patients with non-CC in 33% (14/43), p = 0.016. Patients with mild fi brosis (fi brosis stage 1-2) achieved SVR in 56% (15/27), and patients with advanced fi brosis (fi brosis stage 3 -4) in only 26% (7/27), p = 0.0267. Conclusions: Concentration-guided RBV dosing with darbepoetin support substantially improves tolerance and offers high adherence to a full peg-IFN and RBV treatment course in patients with post-transplant HCV relapse. With this approach genotype 2 and 3 infections can be treated cost-effectively post-transplant. Genotype 1, IL28B non-CC genotype, and advanced fi brosis predicted a low SVR rate.
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| 48. |
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| 49. |
- Gavin, C, et al.
(author)
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Tissue immune profiles supporting response to mesenchymal stromal cell therapy in acute graft-versus-host disease-a gut feeling
- 2019
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In: Stem cell research & therapy. - : Springer Science and Business Media LLC. - 1757-6512. ; 10:1, s. 334-
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Journal article (other academic/artistic)abstract
- Acute graft-versus-host disease (aGvHD), post-allogeneic hematopoietic stem cell transplantation, is associated with high mortality rates in patients not responding to standard line care with steroids. Adoptive mesenchymal stromal cell (MSC) therapy has been established in some countries as a second-line treatment.Limitations in our understanding as to MSC mode of action and what segregates patient responders from non-responders to MSC therapy remain. The principal aim of this study was to evaluate the immune cell profile in gut biopsies of patients diagnosed with aGvHD and establish differences in baseline cellular composition between responders and non-responders to subsequent MSC therapy.Our findings indicate that a pro-inflammatory immune profile within the gut at the point of MSC treatment may impede their therapeutic potential. These findings support the need for further validation in a larger cohort of patients and the development of improved biomarkers in predicting responsiveness to MSC therapy.
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| 50. |
- Hulkko, J, et al.
(author)
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Neph1 is reduced in primary focal segmental glomerulosclerosis, minimal change nephrotic syndrome, and corresponding experimental animal models of adriamycin-induced nephropathy and puromycin aminonucleoside nephrosis
- 2014
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In: Nephron extra. - : S. Karger AG. - 1664-5529. ; 4:3, s. 146-54
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Journal article (peer-reviewed)abstract
- <b><i>Background/Aims:</i></b> The transmembrane proteins Neph1 and nephrin form a complex in the slit diaphragm (SD) of podocytes. As recent studies indicate an involvement of this complex in the polymerization of the actin cytoskeleton and proteinuria, we wanted to study the subcellular localization of Neph1 in the normal human kidney and its expression in focal segmental glomerulosclerosis (FSGS), minimal change nephrotic syndrome (MCNS), and the corresponding experimental models of Adriamycin-induced nephropathy (ADR) and puromycin aminonucleoside nephrosis (PAN). All these disorders are characterized by substantial foot process effacement (FPE) and proteinuria. <b><i>Materials and Methods:</i></b> Kidney biopsies from patients with primary FSGS (perihilar type) and MCNS were compared to normal renal tissue. Mouse and rat kidney cortices from days 7 and 14 after Adriamycin injection and days 2 and 4 after puromycin aminonucleoside injection, respectively, were compared to control mouse and rat kidney. Polyclonal antibodies against Neph1 and nephrin were used for immunoelectron microscopy, and semiquantification was performed. <b><i>Results:</i></b> We localized Neph1 mainly to, and in close proximity to, the SD. Double staining of Neph1 and nephrin showed the proteins to be in close connection in the SD. The total amount of Neph1 in the podocytes was significantly reduced in FSGS, MCNS, ADR, and PAN. The reduction of Neph1 was also seen in areas with and without FPE. Nephrin was reduced in MCNS and PAN but unchanged in FSGS. <b><i>Conclusion:</i></b> With nephrin (but not Neph1) unchanged in FSGS, there might be a disruption of the complex and an involvement of Neph1 in its pathogenesis.
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