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Welcome to "nephro-pathology.com", an educational forum for anyone interested in the specialities of Nephropathology and Nephrology,widely considered among the most challenging and dynamic branches in practice of medicine......
New.................
New images for the Image Quiz 6, Current abstracts; update and links to latest published articles New Topic "Antibody Mediated Rejection" in Literature Guide Nephropath Teaching point- Lambda light chain dominance
These are the results of first nephropath teaching point question " Lambda light chain dominance in DIF studies is a useful diagnostic clue of which glomerular disease". Majority of repondants (47.1%) thought that this would imply monoclonality, IgA nephropathy (which is the correct answer) was a not so close second!
Lai et al had shown that patients with primary IgA nephropathy display a unique immunologic response characterized by a predominance of IgA with lambda light chains in circulation. Same authors also showed the predominance of lambda light-chain IgA1 in the serum of patients with IgA nephropathy and also demonstrated that mesangial IgA deposits in IgA nephropathy consist mainly of IgA with lambda light chains despite the fact that the normal ratio of kappa to lambda light-chain-containing immunoglobulin in human serum is two to one. This lambda light chain predominance is in practice an extremely useful phenomenon, particularly useful when differentiating IgA nephropathy from IgA dominant post infectious glomerulonephritis and in borderline cases with not so intense IgA staining or co-dominant staining of another immunoglobulin sub class! ANCA associated glomerulonephritis and Interleukin 17
Since the discovery of Th17 subtype of CD4+ T cells, extensive insights into the biological role and functions of Interleukin 17 (IL 17) have been gained. IL-17 (or IL-17A) is the founding member of the IL-17 cytokine family and is involved in the induction and mediation of several proinflammatory processes by triggering the expression of many other cytokines such as IL-6 and TNF . In addition to the Th 17 CD4+ T cells, IL 17 is produced by several other hematopoeitic cell types including NK T17 cells,Tc17, NK p46+ cells, Macrophages, Dendritic cells, Paneth cells, Neutrophils and Eosinophils. In context of ANCA associated renal disease, few earlier observations suggested that MPO -ANCA induces IL-17 production by activated neutrophils,via classical complement pathway-dependent manner.However, the exact cellular source of IL 17 in ANCA assoicated glomerulonephritis remained an enigma. To address this issue, Velden et. al in a recent study published in American Journal of Physiology-Renal Physiology have studied the expression of IL 17 in renal biopsies with ANCA associated necrotizing and crescntic glomerulonephritis using a monoclonal antibody against IL 17. The authors detected numerous IL-17-expressing (IL-17+) cells in the glomeruli and tubulointerstitium, most of these being IL-17+ polymorphonuclear neutrophilic granulocytes, with significantly lower numbers of IL-17+ T cells and IL-17+ mast cells. IL-17 was not detected in other infiltrating or resident kidney cells. In the treatment naive patients (those who did not receive immunosuppressive treatment before biopsy), serum creatinine levels were positively correlated with tubulointerstitial IL-17+ neutrophils as well as IL-17+ T cells. As a further proof of their findings, authors have demonstrated that purified human blood neutrophils expressed IL-17 protein and released it upon stimulation in vitro.
These results not only support the previously investigated role for IL-17 in human ANCA-associated glomerulonephritis but also suggest that neutrophils may act as an important early innate source of IL-17, particularly in early phases of the disease , raising the hope that IL-17 may be an important potential target for treating acute ANCA-associated glomerulonephritis. Posted on 28-4-2012 Transglutaminase 2 andIgA nephropathy.....the riddle solved?
IgA nephropathy is recognized as the most common primary glomerulopathy, but has evaded efforts at characterization of molecular and pathophysiological mechanisms that may be targeted for therapeutic interventions. In the recent issue of Journal of Investigative Medicine, Berthelot et al. using genetically humanized mice have uncovered a mechanism for
IgAN pathogenesis that connects receptors for IgA1 with transglutaminase 2 (TGase2)(a molecule that has been previously linked to another autoimmune disease, celiac disease). The authors have shown that while mice expressing both human IgA1 and CD89 (the human IgA Fc receptor) displayed circulating and mesangial deposits of IgA1–sCD89 (soluble CD 89) complexes resulting in kidney inflammation, hematuria, and proteinuria, mice expressing IgA1 only displayed endocapillary IgA1 deposition but neither mesangial injury nor kidney dysfunction. sCD89 injection into IgA1-expressing mouse recipients induced mesangial IgA1 deposits and sCD89 was also detected in patient and mouse mesangium. The authors propose that IgA1 deposition involves a direct binding of sCD89 to mesangial TfR1 (transferrin receptor: CD 71) resulting in TfR1 up-regulation. This interaction induces mesangial surface expression of TGase2 (transglutaminase 2), which in turn up-regulated TfR1 expression forming a pathological amplification loop, resulting in incessant mesangial inflammation and glomerular injury. In the absence of TGase2, IgA1–sCD89 deposits were significantly reduced. Thus it appears that TGase 2 may be the vital link in this cascade which can be targeted for therapeutic interventions. The article has also attracted an editorial published in Science Translational Medicine, where Dr. Obheroi has aptly described this discovery as " Connecting the Dots to Describe a Mechanism for IgA Nephropathy" Posted on 21-4-2012 Laser Microdissection and Mass spectrometry based typing of amyloid deposits
Typing and classification of amyloid deposits in kidneys and
other organs is critical from therapeutic point of view. While many cases are easily classified as AL or secondary amyloidosis based on immunofluorescence and immunohistochemical (SAA) studies, in practice the diagnostic challenges can be significant. The relative insensitivity of immunohistochemistryalong with the occasional weak or equi intense staining of light chains in DIF studies and weak to absent Congo red staining can pose great diagnostic challenges. Over the past few years, the technique of direct mass spectroscopy (MS) based identification of amyloid types in laser micro dissected (LMD) structures from biopsy specimen has shown great promise. In a recent article in Kidney International, Sethi et. al from Mayo Clinic, Rochester present their experience with 127 cases of renal amyloidosis over a three year period, where the technique of LMD –MS was applied to detect amyloid subtypes. The authors conclude that LMD/MS studies are useful because they use formalin fixed paraffin-embedded tissue instead of fresh, frozen, or other specially stored tissue samples. Problematic and challengingbiopsies, such as those with equivocal Congo red staining, equivocal or negative light-chain staining on immunofluorescence studies, heavy-chain component, and less common forms such as fibrinogen Aa, TTR, LECT2,apolipoprotein A-I and A-IV, gelsolin, lysozyme and b-2 microglobulin amyloidosis fall in a group of amyloidosis that can be accurately typed by LMD/MS. Apart from renal amyloidosis this technique has also been successfully applied in amyloid plaques in brain and nerve tissue. Though facilities for LCM and MS are still not available at many institutes, it is hoped that every country wouldeventually develop at least one centre where referral material can be sent for accurate typing of amyloidosis! Posted on 12.4.2012 Journal of Nephropathology
Journal of Nephropathology (JNP), a new peer reviewed tri‐annual medical journal dedicated to the basic and clinical researches in the fields of renal pathology, nephrology, kidney transplantation, renal physiology and hypertension has recently been launched. The journal intends to publish research articles, letters, reviews, short-reviews, invited reviews, editorials, clinical practices, renal pathology images, case reports, commentaries and other associated medical and related articles and personal opinions. It is a welcome step and a clear indicator of the growing clout of Nephropathologists across the world.The journal has an distinguished editorial and advisory board, and we hope that it serves as an important platform for dissemination of research relating to renal pathology and its related specialities. Wishing the editorial committee all the best.........
Posted on 10.4.2012 ASN Kidney Week 2012 abstract submissions are openSubmission of abstracts for ASN Kidney week 2012 are open. The meeting would be held at San Diego, California, USA, from October 30 to November 4, 2012. Detailed information can be obtained from ASN website. The online abstract submissions would be open from April 4 to June 6 2012. A video from abstract submission website can be viewed below...
Pros and cons for C4d as a biomarker
Subsequent to the pioneering work of Feucht et. al, C4d emerged as the"magic marker" for detection of Antibody mediated rejection in allograft biopsies. This finding initiated intense research which has led to better understanding of mechanisms involved in pathogenesis of AMR. In a recent issue of Kidney InternationalCohen et. al. present an excellent overview of the current status of C4d as a biomarker and its possible applications in areas other than allograft pathology. The article discusses the "pros" and "cons" of C4d, the former being relative inexpensive staining technique, ease of performance of staining, easy identification of the diffuse staining pattern and the fact that C4d gives very few false positives (high sensitivity). The "cons" include ineffectiveness in ABO incompatible allografts (which leads to C4d deposition without AMR/graft pathology due to the phenomenon of accomodation), subjective criteria for scoring (issue of focal versus diffuse staining) and its relative insensitivity for diagnosing
chronic/active AMR. In addition,role of C4d in other conditions including systemic autoimmune diseases and pregnancy is also discussed.This review provides an overview of the past, present, and future perspectives of C4d as a biomarker, focusing on its use in solid organ transplantation. A must read for all nephrologists and nephropathologists. Posted on 04-04-2012 Collagenofibrotic glomerulopathy
Collagenofibrotic glomerulopathy (CG) is a rare cause of
nephrotic syndrome characterized by accumulation of atypical Type III collagen fibrils in the mesangial matrix and glomerular subendothelial spaces and elevated serum levels of procollagen III peptide . This disease exhibits indolent progression and has no specific treatment as yet. A recent article by Duggal et al published in Clinical Kidney Journal descibes three new cases and presents an excellent overview of the disease. The cases described in this report as well as majority of previously reported cases/reviews (Yasuda, Alchi, Tamura, Yoshida, Khubchandani , Imbasciati , Gubler, Ferreira) describe the glomerular involvement manifesting as lobular accentuation, variable thickening of capillaries and a membranoproliferative/mesangiocapillary pattern. This along with absence of immune complexes in DIF studies brings various other entities including chronic TMA in the differential diagnosis. A careful morphologic analysis, correct clinical setting and ultrastructural demonstration of abnormally oriented collagen fibrils with a periodicity of about 60 nm clinch the diagnosis. The distribution of these collagen fibrils (and the clinical presentation) separate this entity from nail-patella syndrome, where the abnormal collagen accumulates predominantly in lamina densa of the GBM. The findings in article by Duggal et.al. re-emphasize the fact that collagenofibrotic glomerulopathy should be considered in the setting of a mesangiocapillary/membranoproliferative injury pattern, particularly in absence of demonstrable immune deposits. There is limited experience on transplantation in patients with this disease, however occasional reports suggest a favorable outcome.A case of collagenofibrotic glomerulopathy in virtual microscopy format can be viewed here. Posted on 17.3.2012 First report of CKD registry of India
The first report of CKD registry of India has recently been published in BMC Nephrology. Diabetic nephropathy emerged as the most common culprit, followed by CKD of undetermined etiology, chronic glomerulonephritis and hypertensive nephrosclerosis among others. This report is the first concrete step towards estimation of disease burden of CKD in this part of the world, which appears alarmingly high. This initiative would surely be a stepping stone for policy formulation and regularisation of services towards the CKD community. India, as any other developing country, has had its unique set of obstacles and problems in putting this initiative in place, which are highlighted in this article. Interestingly only about 2% of 54813 submissions in this analysis had a biopsy diagnosis! Another noteworthy aspect of this analysis is the comparison of profiles of patients presenting to public sector hospitals and private hospitals. Predictably, patients from the poorer socioeconomic
category were seen more frequently in public sector hospitals. These patients were significantly younger (p<0.0001) and more frequently presented for the first time in stage V CKD (p<0.0001). In terms of diagnostic categories, patients with CKD of undetermined etiology were more likely seen in public sector hospitals whereas hypertensive nephrosclerosis was more frequently seen in private hospitals (p<0.0001). Importantly, the proportion of patients with diabetic nephropathy was similar in both the groups. Posted on 12-3-2012 The "smokey" pathway to allograft rejection...............
The perils of second hand (passive) smoke are well recognized in terms of neoplastic disorders and cancers. Role of cigarette smoke in renal allograft survival and rejection has been suspected, however a "cause and effect" proof of this association was awaited. In the recent issue of American Journal of Transplantation, Wan et. al publish their experimental study on an islet cell transplantation model where they found that second hand smoke (SHS) hindered long-term islet allograft survival (induced by CD154 costimulatory blockade and donor-specific splenocyte transfusion -DST in recipient mice). In a well designed study, the authors report that SHS suppressed mRNA and protein expression of indoleamine 2, 3-dioxygenase (IDO), which is involved in suppression of T-cell proliferation and acceleration of T-cell apoptosis via the Tryptophan catabolism pathway.IDO overexpression in islet allografts
restored the long-term survival induced by CD154 blockade,thus suggesting that SHS prevents long-term allograft survival by inhibiting IDO expression and activity. Interestingly there was no effect on acute allograft rejection by SHS. This study has strengthened and lended further credibility to observations linking smoking to reduced allograft survival and chronic allograft damage. The seminal article describing the human antigen presenting cells that express indoleamine 2, 3-dioxygenase (IDO) was published in Science in 2002. An excellent review on the role of indoleamine 2,3-dioxygenase in transplantation by Hainz et. al was published some time back in Transplant International and should be read for better understanding of this important biomolecule. Posted on 7-3-2012 
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