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Toulza F, Dominy K, Galliford J, et al., 2019, OR48 Gene expression analysis in renal transplant biopsies: Comparison of split samples and different techniques, American-Society-for-Histocompatibility-and-Immunogenetics (ASHI)/BANFF Joint Scientific Meeting, Publisher: Elsevier, Pages: 52-52, ISSN: 0198-8859
AimThe Banff Classification for Allograft Pathology includes increased expression of genes associated with antibody-mediated rejection (AMR) if thoroughly validated in the diagnostic criteria for AMR. There is limited information on how results of gene expression analysis are influenced by sample preservation (formalin-fixation versus RNA later) and gene analysis technique used. Our aim is to compare: 1) Nanostring analysis of samples from the same biopsy split for formalin fixation and paraffin embedding (FFPE) and RNAlater (RL); 2) Nanostring (NS) and Q-PCR of samples preserved in RL.MethodsWe used a custom panel of 219 genes on the NS platform and of 18 genes for Q-PCR. RNA was extracted from 51 renal transplant biopsies, either from the whole sample (RL), or from 3 × 20-micron sections (FFPE), using a Qiagen kit. Q-PCR was performed with SYBR Green quantification. Correlation was carried out using Spearman rank, with significance set at p < 0.01.ResultsComparing the expression of 219 genes using the NS platform between FFPE and RL samples from the same 51 biopsies, we found significant correlation of the expression of the 219 genes in 47/51 samples (92%) (p median = 4 × 10–12 [3 × 10-56-0.54]); and significant correlation of individual genes between the 2 samples in 163/219 genes (74%) (p median = 0.00003 [3.69 × 10-18-0.98]). Comparing the expression of 18 AMR-tagged genes using NS versus qPCR, from the same pool of RNA in RL (n = 51), we found significant correlation in 17/18 genes (94%) (p median = 0.032 [0.001–0.966]).ConclusionsMost biopsies (92%) can be split and preserved in FFPE or RL and show good correlation of gene expression results across a range of transcripts using a single platform (NS). However almost a quarter of individual genes showed poor correlation on the same platform (NS) between split samples from the same biopsy in FFPE and RL. This could be because there is genuine variation in levels of expressi
Tennekoon H, Cook T, Palmer A, et al., 2019, Congophilic fibrillary glomerulonephritis, Publisher: SPRINGER, Pages: S373-S373, ISSN: 0945-6317
Navaratnarajah A, Sambasivan K, Cook TH, et al., 2019, Predicting long-term renal and patient survival by clinicopathological features in elderly patients undergoing a renal biopsy in a UK cohort, Clinical Kidney Journal, Vol: 12, Pages: 512-520, ISSN: 2048-8505
Background: Several publications have demonstrated the use of renal biopsy in elderly patients in establishing a diagnosis and enabling directed therapy. However, evidence on the long-term outcomes following biopsies is lacking. The aim of this study is to describe the renal and patient outcomes in elderly patients according to indication for biopsy, clinical parameters and the histological diagnosis. Methods: We performed a retrospective cohort study of 463 patients >70 years old who underwent a renal biopsy at our centre between 2006 and 2015. Results: The median age of the patients was 74.8 (range 70.0-89.6) years. The most frequent primary diagnoses were pauci-immune crescentic glomerulonephritis (GN; 12%), acute interstitial nephritis (10.8%) and membranous GN (7.1%). Death-censored renal survival at 1 and 5 years following the index biopsy was 85.2 and 75.9%, respectively, and patient survival at 1 and 5 years was 92.2 and 71.6%, respectively. Patients who progressed to end-stage renal disease (ESRD) were at higher risk of dying compared with patients who did not require dialysis [hazard ratio 2.41 (95% confidence interval 1.58-3.68; P < 0.001]. On multivariate analysis, factors associated with the risk of progression to ESRD were creatinine (P < 0.001), heavy proteinuria (P = 0.002) and a non-chronic kidney disease (CKD) biopsy indication (P = 0.006). A histological diagnosis of primary GN (P = 0.001) or tubulointerstitial nephritis (P = 0.008) was associated with a favourable renal outcome, while patients with vasculitis and paraprotein-related renal disease (PPRD) had the highest risk of requiring dialysis (P = 0.0002 and P = 0.003, respectively). PPRD was also an independent risk factor for death. Conclusions: This study demonstrates that renal biopsies in the elderly not only enable directed therapy, but also provide prognostic i
Foschi V, Bortolotti D, Doyle AF, et al., 2019, Analysis of HLA-G expression in renal tissue in lupus nephritis: a pilot study, Lupus, Vol: 28, Pages: 1091-1100, ISSN: 1477-0962
BACKGROUND: The study aimed to investigate whether HLA-G antigen is expressed in the kidneys of patients affected by lupus nephritis (LN) and whether its detection in renal biopsies could be adopted as a marker of treatment response and prognosis. METHODS: Thirty renal biopsies from patients with LN were selected and analyzed through immunohistochemistry. Laboratory and clinical data were retrospectively collected at baseline, 6 and 12 months and at the latest clinical appointment. A number of patients (63.3%) were treated with rituximab (RTX) +/- methylprednisolone in the induction phase. The expression of HLA-G in glomeruli, tubules and infiltrating cells was examined and compared between lupus patients who achieved either complete or partial renal response and those who did not respond to treatment. RESULTS: HLA-G staining was observed in the glomeruli of 20 of 30 samples from patients with LN. The expression of the antigen was detected in podocytes, along glomerular capillary walls, on parietal glomerular epithelial cells and within the juxtaglomerular apparatus. Seventy per cent of patients whose glomeruli expressed HLA-G achieved partial or complete response at 6 months and 75% at the latest available follow up compared with 30% and 40%, respectively, of those who did not show any expression. The pattern of staining in tubules and infiltrating cells was highly variable precluding any clinical correlation. CONCLUSION: This study demonstrates that HLA-G is expressed in renal tissue in LN. Our retrospective data suggest that its expression could correlate with response to treatment.
Pereira M, Chen T-D, Buang N, et al., 2019, Acute iron deprivation reprograms human macrophage metabolism and reduces inflammation in vivo, Cell Reports, Vol: 28, Pages: 498-511.e5, ISSN: 2211-1247
Iron is an essential metal for fine-tuning the innate immune response through macrophage function. An integrative view of transcriptional and metabolic responses generated from iron perturbation in macrophages is lacking. Here we induced acute iron chelation in primary human macrophages and measured their transcriptional and metabolic responses by integrating RNA-sequencing and stable isotope tracing. We show that acute iron deprivation causes an anti-proliferative Warburg transcriptome characterized by an ATF4-dependent signature. Metabolically, iron-deprived human macrophages show an inhibition of oxidative phosphorylation and a concomitant increase in glycolysis, a large increase in glucosederived citrate pools associated with lipid droplet accumulation and modest levels of itaconate production. LPS polarization increases itaconate/succinate ratio and decreases pro-inflammatory cytokine production in iron-deprived macrophages. Acute iron deprivation reduces the severity of macrophage-dependent crescentic glomerulonephritis by limiting glomerular cell proliferation and inducing lipid accumulation in the renal cortex, phenocopying partly the iron-driven metabolic and transcriptional responses. These results suggest that acute iron deprivation has in vivo protective effects, by causing an antiinflammatory immuno-metabolic switch in macrophages.
Barbour SJ, Coppo R, Zhang H, et al., 2019, Evaluating a New International Risk-Prediction Tool in IgA Nephropathy, ISN World Congress of Nephrology, Publisher: AMER MEDICAL ASSOC, Pages: 942-952, ISSN: 2168-6106
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- Citations: 191
Wei W, Tuna S, Keogh MJ, et al., 2019, Germline selection shapes human mitochondrial DNA diversity, Science, Vol: 364, ISSN: 0036-8075
INTRODUCTIONOnly 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear.Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans.RATIONALETo determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals.RESULTSPreviously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between
Kousios A, Storey R, Troy-Barnes E, et al., 2019, Plasmacytoma-like post-transplant lymphoproliferative disease in a disused arterio-venous fistula: the importance of histopathology., Kidney International Reports, Vol: 4, Pages: 749-755, ISSN: 2468-0249
Common causes of swelling in arteriovenous fistulae (AVFs) include thrombosis, infection, aneurysm, and superior vena cava (SVC) obstruction secondary to previous dialysis vascular catheter use. Malignancies confined in AVFs are rare and have been described in case series and case reports, mostly in immunosuppressed patients.1 Patients who undergo transplantation frequently have functioning or nonfunctioning AVFs. The risk of malignancy is increased in this patient group and thus should be considered in patients presenting with symptomatic AVF. The most common histopathological diagnosis is angiosarcoma.1, 2 Plasmacytoma-like posttransplant lymphoproliferative disease (PTLD) confined in an AVF has not been previously described.
Prendecki M, Mcadoo S, Turner-Stokes T, et al., 2019, THE EFFECT OF P2X7 ANTAGONISM ON NEPHROTOXIC NEPHRITIS, 19th International Vasculitis and ANCA Workshop, Publisher: OXFORD UNIV PRESS, Pages: 93-94, ISSN: 1462-0324
Prendecki M, Mcadoo S, Turner-Stokes T, et al., 2019, A NOVEL P2X7 KNOCKOUT RAT IS NOT PROTECTED FROM EXPERIMENTAL GLOMERULONEPHRITIS OR VASCULITIS, 19th International Vasculitis and ANCA Workshop, Publisher: OXFORD UNIV PRESS, ISSN: 1462-0324
Smith RJH, Appel GB, Blom AM, et al., 2019, C3 glomerulopathy - understanding a rare complement-driven renal disease, NATURE REVIEWS NEPHROLOGY, Vol: 15, Pages: 129-143, ISSN: 1759-5061
Mcadoo S, Prendecki M, Turner-Stokes T, et al., 2019, FOSTAMATINIB TREATMENT OF A NEW MODEL OF MPO-ANCA VASCULITIS IN WKY RATS INDUCED BY ADMINISTRATION OF A SUBNEPHRITOGENIC DOSE OF NEPHROTOXIC SERUM AFTER IMMUNIZATION WITH HUMAN MYELOPEROXIDASE, 19th International Vasculitis and ANCA Workshop, Publisher: OXFORD UNIV PRESS, Pages: 92-92, ISSN: 1462-0324
Wong N, Kang A, Mcadoo S, et al., 2019, MEST-C SCORE IN ADULT HENOCH-SCHONLEIN PURPURA NEPHRITIS, 19th International Vasculitis and ANCA Workshop, Publisher: OXFORD UNIV PRESS, Pages: 51-51, ISSN: 1462-0324
Smith-Jackson K, Yang Y, Denton H, et al., 2019, Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice, Journal of Clinical Investigation, Vol: 129, Pages: 1061-1075, ISSN: 0021-9738
Atypical hemolytic uremic syndrome (aHUS) is frequently associated in humans with loss-of-function mutations in complement-regulating proteins or gain-of-function mutations in complement-activating proteins. Thus, aHUS provides an archetypal complement-mediated disease with which to model new therapeutic strategies and treatments. Herein, we show that, when transferred to mice, an aHUS-associated gain-of-function change (D1115N) to the complement-activation protein C3 results in aHUS. Homozygous C3 p.D1115N (C3KI) mice developed spontaneous chronic thrombotic microangiopathy together with hematuria, thrombocytopenia, elevated creatinine, and evidence of hemolysis. Mice with active disease had reduced plasma C3 with C3 fragment and C9 deposition within the kidney. Therapeutic blockade or genetic deletion of C5, a protein downstream of C3 in the complement cascade, protected homozygous C3KI mice from thrombotic microangiopathy and aHUS. Thus, our data provide in vivo modeling evidence that gain-of-function changes in complement C3 drive aHUS. They also show that long-term C5 deficiency is not accompanied by development of other renal complications (such as C3 glomerulopathy) despite sustained dysregulation of C3. Our results suggest that this preclinical model will allow testing of novel complement inhibitors with the aim of developing precisely targeted therapeutics that could have application in many complement-mediated diseases.
Kousios A, Duncan N, Tam FWK, et al., 2019, Proliferative glomerulonephritis with monoclonal Ig deposits (PGNMID): diagnostic and treatment challenges for the nephrologist!, Kidney International, Vol: 95, Pages: 467-468, ISSN: 0085-2538
Floege J, Barbour SJ, Cattran DC, et al., 2019, Management and treatment of glomerular diseases (part 1): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference, Publisher: ELSEVIER SCIENCE INC, Pages: 268-280, ISSN: 0085-2538
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- Citations: 166
Rovin BH, Caster DJ, Cattran DC, et al., 2019, Management and treatment of glomerular diseases (part 2): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference, Publisher: ELSEVIER SCIENCE INC, Pages: 281-295, ISSN: 0085-2538
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- Citations: 107
Koutroutsos K, Charif R, Moran L, et al., 2019, Successful management of post-transplant focal segmental glomerulosclerosis with therapeutic plasma exchange and rituximab, Clinical and Experimental Nephrology, ISSN: 1342-1751
BACKGROUND: Post-transplant focal segmental glomerulosclerosis (FSGS) is associated with renal allograft loss. Currently, optimal treatment remains controversial. METHODS: The aim of our study was to examine the efficacy and safety of therapeutic plasma exchange (TPE), and rituximab (RTX), in the management of post-transplant FSGS. The treatment protocol consisted of RTX and monthly cycles of 5 plasma exchanges for 6 months. We treated 10 transplant recipients with biopsy-proven post-transplant FSGS. Lastly, we compared the studied group to a historic control group of nine patients with post-transplant FSGS. RESULTS: 9 out of 10 patients achieved remission after the conclusion of treatment (4 complete and 5 partial), while 1 patient did not respond to treatment. During the follow-up period, there was one graft loss and one patient died while in remission from unrelated complications. There was a significant reduction in mean uPCR between diagnosis (517.4 ± 524.2 mg/mmol) and last follow-up (87 ± 121.6 mg/mmol) in the patients with sustained remission (p = 0.026). There was no significant decline in eGFR in the eight relapse-free responders at the end of follow-up. (54.4 ± 16.7 from 49.8 ± 20.4 ml/min) (p = 0.6) An increased response rate to the combined TPE and RTX treatment was demonstrated, when compared to a historic control group of nine patients with post-transplant FSGS, as only five out of nine patients achieved remission (two complete and three partial) in that group. CONCLUSIONS: In this study, treatment with TPE and RTX appears to be safe, well tolerated and effective in the management of patients with post-transplant FSGS.
Wilson HR, Medjeral-Thomas NR, Gilmore AC, et al., 2019, Glomerular membrane attack complex is not a reliable marker of ongoing C5 activation in lupus nephritis, Kidney International, Vol: 95, Pages: 655-665, ISSN: 0085-2538
Complement plays an important role in the pathogenesis of lupus nephritis (LN). With the emergence of therapeutic complement inhibition, there is a need to identify patients in whom complement-driven inflammation is a major cause of kidney injury in LN. Clinical and histopathological data were obtained retrospectively from 57 biopsies with class III, IV, and V LN. Biopsies were stained for complement components C9, C5b-9, C3c, and C3d and for the macrophage marker CD68. C9 and C5b-9 staining were highly correlated (r = 0.92 in the capillary wall). C5b-9 staining was detected in the mesangium and/or capillary wall of both active and chronic proliferative LN in all but one biopsy and in the capillary wall of class V LN in all biopsies. C5b-9 staining intensity in the tubular basement membrane correlated with markers of tubulointerstitial damage, and more intense capillary wall C5b-9 staining was significantly associated with nonresponse to conventional treatment. Glomerular C5b-9 staining intensity did not differ between active and chronic disease; in contrast, C3c and CD68 staining were associated with active disease. Evaluation of serial biopsies and comparison of staining in active and chronic LN demonstrated that C5b-9 staining persisted for months to years. These results suggest that C5b-9 staining is almost always present in LN, resolves slowly, and is not a reliable marker of ongoing glomerular C5 activation. This limits the utility of C5b-9 staining to identify patients who are most likely to benefit from C5 inhibition.
Dominy KM, Willicombe M, Al Johani T, et al., 2019, Molecular assessment of C4d positive renal transplant biopsies without evidence of rejection, Kidney International Reports, Vol: 4, Pages: 148-158, ISSN: 2468-0249
IntroductionImmunohistochemical staining for C4d in peritubular capillaries has been part of antibody-mediated rejection (AbMR) definition in the Banff Classification for Allograft Pathology since 2003. However, it has limited sensitivity and specificity, therefore the clinical significance of C4d-positive biopsies without evidence of rejection (C4d+ WER) is unknown. We investigated the transcript levels of genes associated with AbMR in C4d+ WER biopsies from both ABO-compatible and incompatible renal transplant patients.MethodsRNA was extracted from formalin-fixed paraffin-embedded renal transplant biopsies (n = 125) and gene expression analysis of 35 AbMR-associated transcripts carried out using the NanoString nCounter system.ResultsAbMR-associated transcripts were significantly increased in samples with AbMR or suspicious AbMR. A subgroup of 17 of 35 transcripts that best distinguished AbMR from C4d-negative biopsies without evidence of rejection was used to study C4d+ WER samples. There was no differential expression between C4d-negative and C4d+ WER from both ABO-incompatible and -compatible transplants. The geometric mean of 17 differentially expressed genes was used to assign the C4d+ WER biopsies a high- or low-AbMR transcript score. Follow-up biopsies showed AbMR within 1 year of initial biopsy in 5 of 7 high-AbMR transcript patients but only 2 of 46 low-AbMR transcript patients. In multivariate logistic regression analysis, elevated transcript levels in a C4d+ WER biopsy were associated with increased odds for biopsy-proven AbMR on follow-up (P = 0.032, odds ratio 16.318), whereas factors including donor-specific antibody (DSA) status and time since transplantation were not.ConclusionGene expression analysis in C4d+ WER samples has the potential to identify patients at higher risk of developing AbMR.
Smith-Jackson K, Yang Y, Denton H, et al., 2018, CS deficiency protects ageing C3 gain-of-function mice from renal injury despite significant C3 deposition in the kidney, 27th International Complement Workshop (ICW), Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 187-187, ISSN: 0161-5890
Sadeghi-Alavijeh O, Henderson S, Bass P, et al., 2018, Crescentic glomerulonephritis with anti-GBM antibody but no glomerular deposition, BMC Nephrology, Vol: 19, ISSN: 1471-2369
BackgroundAnti-glomerular basement membrane (GBM) antibodies are highly specific for Goodpasture’s or anti-GBM disease, in which they are generally directed against the non-collagenous (NC1) domain of the alpha 3 chain of type IV collagen(α3(IV)), and less commonly, toward the α 4(IV) or α 5(IV) chains, which form a triple helical structure in GBM and alveolar basement membrane (ABM). Alterations in the hexameric structure of the NC1 (α3 (IV)), allows novel epitopes to be exposed and an immune response to develop, with subsequent linear antibody deposition along the GBM, leading to a crescentic glomerulonephritis. Positive anti-GBM antibodies are assumed to be pathogenic and capable of binding GBM in vivo, especially in the context of rapidly progressive glomerulonephritis.We have investigated patients with circulating anti-GBM antibodies, reactive to α3 (IV) and human GBM by immunoassays and Western blotting respectively, with focal necrotising crescentic glomerulonephritis but no linear GBM antibody deposition on immunohistochemistry. Three out of four were also ANCA positive. Despite not binding native GBM, patients’ sera showed linear binding to primate glomeruli by indirect immunofluorescence, in the 2 cases tested. Following treatment, significant improvements in kidney function were found in 3/4 patients.Case presentationWe present four patients with crescentic glomerulonephritis and circulating anti-GBM antibodies, but no glomerular binding.ConclusionsThese novel findings, demonstrate that in some patients anti-GBM antibodies may not bind their own GBM. This has important implications for clinical diagnosis, suggesting that histological confirmation of kidney injury by anti-GBM antibodies should be obtained, as non-binding GBM antibodies may be associated with significant renal recovery.
Roufosse CA, Willicombe M, Galliford J, et al., 2018, C4d Positive Renal Transplant Biopsies With No other Evidence of Rejection: Transcriptional Investigation of Biological Significance Using Nanostring nCounter Technology, 11th Joint Meeting of the British-Division of the International-Academy-of-Pathology and the Pathological-Society-of-Great-Britain-and-Ireland, Publisher: WILEY, Pages: S18-S18, ISSN: 0022-3417
Roufosse C, Willicombe M, Al Johani T, et al., 2018, Molecular assessment of C4d positive renal transplant biopsies without evidence of rejection, Publisher: SPRINGER, Pages: S15-S16, ISSN: 0945-6317
Kousios A, Brah T, Troy-Barnes E, et al., 2018, The Histopathological Spectrum of Monoclonal Gammopathies of Renal Significance: A Single Centre Experience, 11th Joint Meeting of the British-Division of the International-Academy-of-Pathology and the Pathological-Society-of-Great-Britain-and-Ireland, Publisher: WILEY, Pages: S19-S19, ISSN: 0022-3417
Roufosse C, Brah T, Troy-Barnes E, et al., 2018, The histopathological spectrum of monoclonal gammopathies of renal significance: a single centre experience, Publisher: SPRINGER, Pages: S81-S81, ISSN: 0945-6317
Roufosse CA, Webster P, Moss J, et al., 2018, Familial Fibrillary Glomerulonephritis with Positive Immunohistochemistry for DNAJB9, 11th Joint Meeting of the British-Division of the International-Academy-of-Pathology and the Pathological-Society-of-Great-Britain-and-Ireland, Publisher: WILEY, Pages: S38-S38, ISSN: 0022-3417
Alexander S, John GT, Korula A, et al., 2018, Protocol and rationale for the first South Asian 5-year prospective longitudinal observational cohort study and biomarker evaluation investigating the clinical course and risk profile of IgA nephropathy: GRACE IgANI cohort [version1; referees: 2 approved], Wellcome Open Research, Vol: 3, ISSN: 2398-502X
Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis and an important cause of end-stage kidney disease. Unlike the slowly progressive course seen among Caucasian and East Asian subjects (actuarial survival 80-85% over 10 years), in India about 30-40% of patients have nephrotic syndrome and renal dysfunction at presentation and a 10-year renal survival of 35%, as reported from a retrospective registry. These observations cannot be entirely attributed to a lack of uniform screening protocols or late referral and attest to the probability that IgAN may not be the same disease in different parts of the world. Methods: We will prospectively recruit 200 patients with IgAN (the GRACE IgANI- Glomerular Research And Clinical Experiments- Ig ANephropathy in Indians-cohort) and stratify them into low and high risk of progression based on published absolute renal risk scores. We will test the validity of this risk score in an unselected Indian IgAN population over a 5-year follow-up period. In parallel, we will undertake extensive exploratory serum, urine, renal and microbiome biomarker studies, firstly, to determine if the underlying pathogenic pathways are the same in Indian IgAN compared to those reported in Caucasian and East Asian IgAN. Secondly, we will systematically assess the value of measuring selected biomarkers and adding this data to traditional measures of risk in IgAN to predict kidney failure. We ultimately hope to generate a composite IgAN risk score specific for the Indian population. Ethics and data dissemination: Approval was obtained from the Institutional Review Board (Silver, Research and Ethics Committee) of the Christian Medical College, Vellore, India (Ref. No. IRB Min. No. 8962 [Other] dated 23.07.2014 and IRB Min. No. 9481 [Other] dated 24.06.2015). It is anticipated that results of this study will be presented at national and international meetings, with reports being published from late 2018.
Koskinen AR, Cheng Z-Z, Pickering MC, et al., 2018, Distribution of exogenous complement factor H in mice invivo, Scandinavian Journal of Immunology, Vol: 88, ISSN: 0300-9475
Factor H is an important regulator of complement activation in plasma and on cell surfaces in both humans and mice. If FH function is compromised, inappropriate complement activation on self‐surfaces can have disastrous effects as seen in the kidney diseases atypical haemolytic uremic syndrome (aHUS) and C3 glomerulopathy. As FH constructs have been proposed to be used in treatment for these diseases, we studied the distribution of exogenous FH fragments in mice. Full‐length mFH, mFH1‐5 and mFH18‐20 fragments were radiolabelled, and their distribution was examined in WT, FH−/− and FH−/−C3−/− mice in vivo. Whole body scintigraphy revealed accumulation of radioactivity in the abdominal part of the mice, but also to the thyroid gland and urinary bladder. At organ level in WT mice, some full‐length FH accumulated in internal organs, but most of it remained in the circulation. Both of the mFH fragments accumulated in the kidneys and were excreted in urine. For mFH1‐5, urinary secretion is the likely cause for the accumulation. Concentration of mFH18‐20 to kidneys was slower, and at tissue level, mFH18‐20 was localized at the proximal tubuli in WT and FH−/−C3−/− mice. No C3‐independent binding to glomeruli was detected. In conclusion, these results show that glomerular glycosaminoglycans and sialic acids alone do not collect FH in kidneys. Deposition of C3 fragments is also needed, which implies that in aHUS, the problem is in simultaneous recognition of C3 fragments and glycosaminoglycans or sialic acids by FH, not just the inability of FH to recognize glomerular endothelium as such.
Saja M, Cook HT, Ruseva M, et al., 2018, A triglyceride-rich lipoprotein environment exacerbates renal injury in the accelerated nephrotoxic nephritis model, Clinical and Experimental Immunology, Vol: 192, Pages: 337-347, ISSN: 1365-2249
Hyperlipidaemia accompanies chronic renal disease either as a consequence of the renal dysfunction or as part of generalized metabolic derangements. Under both situations, the lipid profile is characterized by accumulation of triglyceride‐rich lipoproteins (TGRLs). This lipid profile is recognized as a risk factor for cardiovascular complications. Whether it may pose a risk for renal injury as well remains unclear. A hyper‐TGRL state was generated in C57BL/6 mice using poloxamer‐407 (P‐407) and immune complex‐mediated renal injury was triggered using the accelerated nephrotoxic nephritis (ANTN) model. The hyper‐TGRL animals were hypersensitive to ANTN demonstrated by greater haematuria and glomerular cellularity. These changes were accompanied by increased glomerular accumulation of CD68+ macrophages. The hypersensitive response to ANTN was not seen in low‐density lipoprotein receptor knock‐out mice fed with a high fat diet, where triglyceride levels were lower but cholesterol levels comparable to those obtained using P‐407. These data indicate that a hyper‐TGRL state might be more detrimental to the kidneys than low‐density lipoprotein‐driven hypercholesterolaemia during immune complex‐mediated nephritis. We speculate that the hyper‐TGRL environment primes the kidney to exacerbated renal damage following an inflammatory insult with increased accumulation of macrophages that may play a key role in mediating the injurious effects.
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