Publications
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Bate S, McGovern D, Costigliolo F, et al., 2024, The Improved Kidney Risk Score in ANCA-Associated Vasculitis for Clinical Practice and Trials., J Am Soc Nephrol, Vol: 35, Pages: 335-346
SIGNIFICANCE STATEMENT: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. More than 1500 patients were collated in an international longitudinal study to revise the ANCA kidney risk score. The score showed satisfactory performance, mimicking the original study (Harrell's C=0.779). In the development cohort of 959 patients, no additional parameters aiding the tool were detected, but replacing the GFR with creatinine identified an additional cutoff. The parameter interstitial fibrosis and tubular atrophy was modified to allow wider access, risk points were reweighted, and a fourth risk group was created, improving predictive ability (C=0.831). In the validation, the new model performed similarly well with excellent calibration and discrimination ( n =480, C=0.821). The revised score optimizes prognostication for clinical practice and trials. BACKGROUND: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. A retrospective international longitudinal cohort was collated to revise the ANCA renal risk score. METHODS: The primary end point was ESKD with patients censored at last follow-up. Cox proportional hazards were used to reweight risk factors. Kaplan-Meier curves, Harrell's C statistic, receiver operating characteristics, and calibration plots were used to assess model performance. RESULTS: Of 1591 patients, 1439 were included in the final analyses, 2:1 randomly allocated per center to development and validation cohorts (52% male, median age 64 years). In the development cohort ( n =959), the ANCA renal risk score was validated and calibrated, and parameters were reinvestigated modifying interstitial fibrosis and tubular atrophy allowing semiquantitative reporting. An additional cutoff for kidney function (K) was identified, and serum creatinine replaced GFR (K0: <250 µ mol/L=0, K1: 250-450 µ mol/L=4, K2: >450 µ mol/L=11 points). The risk points for the percentage of normal glom
Stanway J, Brown N, Pervez A, et al., 2024, IgA vasculitis nephritis-outcomes in adult-onset disease., Rheumatology (Oxford)
OBJECTIVES: IgA vasculitis (IgAV) in adults has been relatively under-investigated. Since outcomes are worse in other forms of vasculitis with increasing age, we investigated the outcomes of IgAV comparing younger adults (18-34), middle aged adults (35-64) and elderly patients (≥64 years) focusing on kidney outcomes. METHODS: We identified patients with renal biopsy confirmed IgAV nephritis and collected data regarding clinical features and progression to end stage kidney disease (ESKD). The relationship between patient factors and ESKD was analysed by regression. RESULTS: We identified 202 cases, 34% aged 18-34, 43% aged 35-64 and 23% were elderly (>64 years). Median follow up was 44 months. Elderly patients were more likely to present with ESKD (23.9%) compared with middle aged (13.7%) and younger adults (2.9%)(χ2 11.6, p= 0.002). In patients with independent kidney function at biopsy, there was no difference in outcomes between age groups. Male gender, Black ethnicity, diabetes, histological evidence of chronic renal damage and eGFR < 30mls/min were risk factors for development of ESKD. In this observational study 68.3% of patients received glucocorticoids and 56.9% additional immunosuppression. CONCLUSIONS: Elderly patients with IgAV are more likely to have ESKD at presentation, but there is no difference in renal survival between age groups, among those presenting with independent renal function. Renal impairment at biopsy is an independent risk factor for subsequent development of ESKD. There is significant variability in the timing of kidney biopsy and management of these patients among specialist centres. Young adults have outcomes more in keeping with childhood IgAV.
Pendolino AL, Benshetrit G, Navaratnam AV, et al., 2023, The role of ANCA in the management of cocaine-induced midline destructive lesions or ENT pseudo-granulomatosis with polyangiitis: a London multicentre case series., Laryngoscope
OBJECTIVE: In this multicentric study involving three London hospitals, we compared ANCA-positive and ANCA-negative cocaine-induced midline destructive lesions (CIMDL) patients to assess how presence of antineutrophil cytoplasmic antibodies (ANCA) may correlate with disease severity. Our secondary aims are to better classify etiology centered around ANCA positivity and, consequently, better disease management. METHODS: A retrospective review was performed to identify patients with CIMDL seen between January 2019 and December 2022. Population data including age, sex, presentation, endoscopic findings, duration of cocaine use and active use of cocaine, type of treatment, laboratory (including ANCA serology), radiological, and histological findings were collected. RESULTS: Forty CIMDL patients (25 male, median age of 42 years) were identified. The majority of them (72.5%) presented with either a septal perforation, a saddle nose deformity (22.5%), and/or a palatal fistula (20.0%). ANCA was positive in 71.1% of cases (66.7% p-ANCA). No statistically significant differences in the general characteristics, type of treatment, laboratory results, radiological or histological findings were observed when comparing ANCA-positive and ANCA-negative CIMDL patients or when comparing p-ANCA and c-ANCA patients. Similarly, no statistically significant difference was obtained when comparing the pattern of distribution of lesions between the two groups. CONCLUSIONS: A large percentage of CIMDL patients showed positive ANCA test (71.1%) and in the majority of the cases a p-ANCA pattern specifically targeting PR3 (p-ANCA, PR3 + MPO-). However, ANCA positivity or presence of a specific ANCA pattern was not associated with more severe presentation or more aggressive disease. Given its similarities to granulomatosis with polyangiitis (GPA), we recommend the use of the term "cocaine-induced ENT pseudo-GPA" instead of CIMDL. LEVEL OF EVIDENCE: IV Laryngosc
Moiseev S, Bulanov N, Crnogorac M, et al., 2023, Traditional and Disease-Specific Risk Factors for Cardiovascular Events in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Multinational Retrospective Study., J Rheumatol, Vol: 50, Pages: 1145-1151
OBJECTIVE: To investigate the occurrence of cardiovascular events (CVEs) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, China, Turkey, Russia, the United Kingdom, and the USA. METHODS: Patients with a definite diagnosis of AAV who were followed for ≥ 3 months and had sufficient documentation were included. Data on myocardial infarction (MI) and stroke were collected retrospectively from tertiary vasculitis centers. Univariate and multivariate Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: Over a median follow-up of 62.0 months (IQR 22.6-100.0), CVEs (mostly MIs) occurred in 245 (10.7%) of 2286 patients with AAV, with a higher frequency in China and the UK. On multivariate regression analysis, older age (55-64.9 yrs, HR 2.93, 95% CI 1.99-4.31), smoking (HR 1.98, 95% CI 1.48-2.64), Chinese origin (HR 4.24, 95% CI 3.07-5.85), and pulmonary (HR 1.50, 95% CI 1.09-2.06) and kidney (HR 3.02, 95% CI 2.08-4.37) involvement were independent variables associated with a higher occurrence of CVEs. CONCLUSION: We showed that geographic region and both traditional and disease-specific (kidney involvement in particular) factors were independently associated with CVEs. Proper assessment and management of modifiable cardiovascular (CV) risk factors are essential for prevention of CV morbidity in patients with AAV.
Smith RM, Jones RB, Specks U, et al., 2023, Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial, ANNALS OF THE RHEUMATIC DISEASES, Vol: 82, Pages: 937-944, ISSN: 0003-4967
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- Citations: 5
Gulati K, Pusey CD, 2023, Plasma exchange as an adjunctive therapy in anti-neutrophil cytoplasm antibody-associated vasculitis, EXPERT REVIEW OF CLINICAL IMMUNOLOGY, Vol: 19, Pages: 417-430, ISSN: 1744-666X
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- Citations: 1
Floyd L, Bate S, Hadi Kafagi A, et al., 2023, Risk Stratification to Predict Renal Survival in Anti-Glomerular Basement Membrane Disease, JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 34, Pages: 505-514, ISSN: 1046-6673
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- Citations: 6
Prendecki M, Gulati K, Pisacano N, et al., 2023, Syk activation in circulating and tissue innate immune cells in antineutrophil cytoplasmic antibody-associated vasculitis, Arthritis and Rheumatology, Vol: 75, Pages: 84-97, ISSN: 2326-5205
OBJECTIVE: Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG-mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA-induced myeloid cell activation and vasculitis pathogenesis. METHODS: Phosphorylation of Syk in myeloid cells from healthy controls and ANCA-associated vasculitis (AAV) patients was analyzed using flow cytometry. The effect of Syk inhibition on myeloperoxidase (MPO)-ANCA IgG activation of cells was investigated using functional assays (interleukin-8 and reactive oxygen species production) and targeted gene analysis with NanoString. Total and phosphorylated Syk at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridization. RESULTS: We identified increased phosphorylated Syk at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to patients with disease in remission or healthy controls. Syk was phosphorylated in vitro following MPO-ANCA IgG stimulation, and Syk inhibition was able to prevent ANCA-mediated cellular responses. Using targeted gene expression analysis, we identified up-regulation of FcR- and Syk-dependent signaling pathways following MPO-ANCA IgG stimulation. Finally, we showed that Syk is expressed and phosphorylated in tissue leukocytes at sites of organ inflammation in AAV. CONCLUSION: These findings indicate that Syk plays a critical role in MPO-ANCA IgG-induced myeloid cell responses and that Syk is activated in circulating immune cells and tissue immune cells in AAV; therefore, Syk inhibition may be a potential therapeutic option.
Pisacano N, McAdoo SP, Guck J, et al., 2022, Biomechanical Phenotype of Circulating Neutrophils Is Altered in ANCA Associated Vasculitis, Publisher: WILEY, Pages: 3359-3361, ISSN: 2326-5191
Jayne D, Walsh M, Merkel PA, et al., 2022, Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT, HEALTH TECHNOLOGY ASSESSMENT, Vol: 26, Pages: 1-+, ISSN: 1366-5278
Jayne D, Walsh M, Merkel PA, et al., 2022, Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT, HEALTH TECHNOLOGY ASSESSMENT, Vol: 26, ISSN: 1366-5278
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- Citations: 3
Prendecki M, McAdoo SP, Turner-Stokes T, et al., 2022, Glomerulonephritis and autoimmune vasculitis are independent of P2RX7 but may depend on alternative inflammasome pathways., Journal of Pathology, Vol: 257, ISSN: 0022-3417
P2RX7, an ionotropic receptor for extracellular ATP, is expressed on immune cells, including macrophages, monocytes and dendritic cells and is up-regulated on non-immune cells following injury. P2RX7 plays a role in many biological processes, including production of pro-inflammatory cytokines such as IL-1β via the canonical inflammasome pathway. P2RX7 has been shown to be important in inflammation and fibrosis and may also play a role in autoimmunity. We have developed and phenotyped a novel P2RX7 knock-out (KO) inbred rat strain and taking advantage of the human-resembling unique histopathological features of rat models of glomerulonephritis, we induced three models of disease: nephrotoxic nephritis, experimental autoimmune glomerulonephritis, and experimental autoimmune vasculitis. We found that deletion of P2RX7 does not protect rats from models of experimental glomerulonephritis or the development of autoimmunity. Notably, treatment with A-438079, a P2RX7 antagonist, was equally protective in WKY WT and P2RX7 KO rats, revealing its 'off-target' properties. We identify a novel ATP/P2RX7/K+ efflux-independent and caspase-1/8-dependent pathway for production of IL-1β in rat dendritic cells, which was absent in macrophages. Taken together, these results comprehensively establish that inflammation and autoimmunity in glomerulonephritis is independent of P2RX7 and reveals the off-target properties of drugs previously known as selective P2RX7 antagonists. Rat mononuclear phagocytes may be able to utilise an 'alternative inflammasome' pathway to produce IL-1β independently of P2RX7, which may account for the susceptibility of P2RX7 KO rats to inflammation and autoimmunity in glomerulonephritis. This article is protected by copyright. All rights reserved.
Gulati K, Edwards H, Prendecki M, et al., 2022, Whether the addition of high-dosage methylprednisolone to plasma exchange was more effective than plasma exchange in the treatment for severe antineutrophil cytoplasmic antibody-associated vasculitis? reply, KIDNEY INTERNATIONAL, Vol: 101, Pages: 648-649, ISSN: 0085-2538
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Falcone S, Nicol T, Blease A, et al., 2022, A novel model of nephrotic syndrome results from a point mutation in <i>Lama5</i> and is modified by genetic background, Publisher: ELSEVIER SCIENCE INC, Pages: 527-540, ISSN: 0085-2538
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- Citations: 3
Tempest-Roe S, Prendecki M, McAdoo S, et al., 2022, Inhibition of spleen tyrosine kinase decreases donor specific antibody levels in a rat model of sensitization, Scientific Reports, Vol: 12, ISSN: 2045-2322
Antibody mediated rejection is a major cause of renal allograft loss. Circulating preformed donor specific antibodies (DSA) can result as a consequence of blood transfusion, pregnancy or prior transplantation. Current treatment strategies are limited due to partial or transient efficacy, adverse side-effects or patient unsuitability. Previous in vivo studies exploring autoimmune diseases have shown that spleen tyrosine kinase (SYK) signalling is involved in the development of pathogenic autoantibody. The role of SYK in allogenic antibody production is unknown, and we investigated this in a rodent model of sensitization, established by the transfusion of F344 whole blood into LEW rats. Two-week treatment of sensitized rats with selective SYK inhibitor fostamatinib strongly blocked circulating DSA production without affecting overall total immunoglobulin levels, and inhibition was sustained up to 5 weeks post-completion of the treatment regimen. Fostamatinib treatment did not affect mature B cell subset or plasma cell levels, which remained similar between non-treated controls, vehicle treated and fostamatinib treated animals. Our data indicate fostamatinib may provide an alternative therapeutic option for patients who are at risk of sensitization following blood transfusion while awaiting renal transplant.
Walsh M, Collister D, Zeng L, et al., 2022, The effects of plasma exchange in patients with-ANCA-associated vasculitis: an updated systematic review and -meta-analysis, BMJ-BRITISH MEDICAL JOURNAL, Vol: 376, ISSN: 0959-535X
Page TH, Chiappo D, Brunini F, et al., 2022, Danger-associated molecular pattern molecules and the receptor for advanced glycation end products enhance ANCA-induced responses, RHEUMATOLOGY, Vol: 61, Pages: 834-845, ISSN: 1462-0324
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- Citations: 7
Woollard K, 2022, Chronic kidney disease mediates cardiac dysfunction associated with increased resident cardiac macrophages, BMC Nephrology, Vol: 23, Pages: 1-15, ISSN: 1471-2369
Background – The leading cause of death in end-stage kidney disease is related tocardiovascular disease. Macrophages are known to be involved in both chronic kidney disease(CKD) and heart failure, however their role in the development of cardiorenal syndrome is lessclear. We thus sought to investigate the role of macrophages in uremic cardiac disease.Methods – We assessed cardiac response in two experimental models of CKD and testedmacrophage and chemokine implication in monocytopenic CCR2-/- and anti-CXCL10 treatedmice. We quantified CXCL10 in human CKD plasma and tested the response of human iPSCderived cardiomyocytes and primary cardiac fibroblasts to serum from CKD donors. Results– We found that reduced kidney function resulted in the expansion of cardiac macrophages,in particular through local proliferation of resident populations. Influx of circulating monocytescontributed to this increase. We identified CXCL10 as a crucial factor for cardiac macrophageexpansion in uremic disease. In humans, we found increased plasma CXCL10 concentrationsin advanced CKD, and identified the production of CXCL10 in cardiomyocytes and cardiacfibroblasts. Conclusions – This study provides new insight into the role of the innate immunesystem in uremic cardiomyopathy.
Prendecki M, Pusey CD, 2022, Tubulointerstitial Nephritis Due to Autoimmune Diseases, Tubulointerstitial Nephritis, Pages: 81-101, ISBN: 9783030934378
Tubulointerstitial nephritis (TIN) is a histopathological feature of many systemic and autoimmune diseases including sarcoidosis, Sjogren’s syndrome, systemic lupus erythematosus (SLE), tubulointerstitial nephritis and uveitis syndrome (TINU), and ANCA-associated vasculitis (AAV). It can occur as a secondary phenomenon due to the presence of glomerular inflammation or can be present in isolation. The presence and severity of tubulointerstitial injury has been shown in several conditions to be of greater use in predicting kidney prognosis than the severity of glomerular injury; despite this TIN is often overlooked in diagnostic classifications. The pathogenesis of TIN in the absence of glomerular inflammation is incompletely understood but there may be mechanisms in common regardless of the underlying systemic disease. Treatment is usually with corticosteroids and other immunosuppressive agents but prognosis is variable, depending on the disease.
Gulati K, Edwards H, Prendecki M, et al., 2021, Combination treatment with rituximab, low-dose cyclophosphamide and plasma exchange for severe antineutrophil cytoplasmic antibody-associated vasculitis, Kidney International, Vol: 100, Pages: 1316-1324, ISSN: 0085-2538
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis can present with life-threatening lung-kidney syndromes. However, many controlled treatment trials excluded patients with diffuse alveolar hemorrhage or severely impaired glomerular filtration rates, and so the optimum treatment in these cases is unclear. In this retrospective cohort study, we report the outcomes of 64 patients with life-threatening disease treated with a combination regimen of rituximab, low-dose intravenous cyclophosphamide, oral glucocorticoids, and plasma exchange. At entry, the median estimated glomerular filtration rate was 9 mL/min, 47% of patients required dialysis, and 52% had diffuse alveolar hemorrhage. All patients received a minimum of seven plasma exchanges, and the median cumulative doses of rituximab, cyclophosphamide, and glucocorticoid were 2, 3, and 2.6 g, respectively, at six months. A total of 94% of patients had achieved disease remission (version 3 Birmingham Vasculitis Activity Score of 0) at this time point, and 67% of patients who required dialysis recovered independent kidney function. During long-term follow-up (median duration 46 months), overall patient survival was 85%, and 69% of patients remained free from end-stage kidney disease, which compares favorably to a historic cohort with severe disease treated with a conventional induction regimen. Combination treatment was associated with prolonged B cell depletion and low rates of relapse; 87% of patients were in continuous remission at month 36. The serious infection rate during total follow-up was 0.28 infections/patient/year, suggesting that combination treatment is not associated with an enduring risk of infection. Thus, we suggest that combination immunosuppressive therapy may permit glucocorticoid avoidance and provide rapid and prolonged disease control in patients with severe ANCA-associated vasculitis.
Moiseev S, Kronbichler A, Makarov E, et al., 2021, Association of venous thromboembolic events with skin, pulmonary and kidney involvement in ANCA-associated vasculitis: a multinational study, RHEUMATOLOGY, Vol: 60, Pages: 4654-4661, ISSN: 1462-0324
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- Citations: 12
Prendecki M, Gulati K, Turner-Stokes T, et al., 2021, Characterisation of an enhanced preclinical model of experimental MPO-ANCA autoimmune vasculitis, Journal of Pathology, Vol: 255, Pages: 107-119, ISSN: 0022-3417
Experimental autoimmune vasculitis (EAV) is a model of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) induced by immunisation of susceptible rat strains with myeloperoxidase (MPO). Animals develop circulating MPO-ANCA, pulmonary haemorrhage and glomerulonephritis, although renal injury is mild and recovers spontaneously without treatment. In this study we aimed to augment the severity of glomerulonephritis. Following induction of EAV on day 0, a sub-nephritogenic dose of nephrotoxic serum (NTS) containing heterologous antibodies to glomerular basement membrane was administered on day 14. This resulted in a significant increase in disease severity at day 28 compared to MPO immunisation alone - with more urinary abnormalities, infiltrating glomerular leucocytes, and crescent formation that progressed to glomerular and tubulointerstitial scarring by day 56, recapitulating important features of human disease. Importantly, the glomerulonephritis remained pauci-immune, and was strictly dependent on the presence of autoimmunity to MPO, as there was no evidence of renal disease following administration of sub-nephritogenic NTS alone or after immunisation with a control protein in place of MPO. Detailed phenotyping of glomerular leucocytes identified an early infiltrate of non-classical monocytes following NTS administration that, in the presence of autoimmunity to MPO, may initiate the subsequent influx of classical monocytes which augment glomerular injury. We also showed that this model can be used to test novel therapeutics by using a small molecule kinase inhibitor (fostamatinib) that rapidly attenuated both glomerular and pulmonary injury over a four-day treatment period. We believe that this enhanced model of MPO-AAV will prove useful for the study of glomerular leucocyte behaviour and novel therapeutics in AAV in the future. This article is protected by copyright. All rights reserved.
Vallant N, Wolfhagen N, Sandhu B, et al., 2021, A Comparison of Pulsatile Hypothermic and Normothermic Ex Vivo Machine Perfusion in a Porcine Kidney Model, TRANSPLANTATION, Vol: 105, Pages: 1760-1770, ISSN: 0041-1337
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- Citations: 9
Medjeral-Thomas NR, Pusey CD, 2021, New Insights into Epidemiology and Outcome of Bacterial Infection?Related Glomerulonephritis, CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 16, Pages: 1149-1151, ISSN: 1555-9041
Teng YKO, Pusey CD, Vaglio A, et al., 2021, Editorial: Immune Monitoring Responses in Renal Autoimmune Diseases, FRONTIERS IN IMMUNOLOGY, Vol: 12, ISSN: 1664-3224
Boharoon H, Tomlinson J, Limback-Stanic C, et al., 2021, A case series of patients with isolated IgG4-related hypophysitis treated with rituximab, Journal of the Endocrine Society, Vol: 4, Pages: 1-9, ISSN: 2472-1972
ContextThe acute presentation of Immunoglobulin G4 (IgG4)-related hypophysitis can be indistinguishable from other forms of acute hypophysitis and histology remains the diagnostic gold standard. The high recurrence rate necessitates long term immunosuppressive therapy. Rituximab (RTX) has been shown to be effective in systemic IgG4-related disease (IgG4-RD), but experience with isolated pituitary involvement remains limited.Case descriptionWe report three female patients with MRI findings suggestive of hypophysitis. All patients underwent transsphenoidal biopsy and fulfilled diagnostic criteria for IgG4-related hypophysitis. Treatment with GCs (GC) resulted in good therapeutic response in patients 1 and 2, but the disease recurred on tapering doses of GCs. GC treatment led to emotional lability in Patient 3 necessitating dose reduction. All three patients received RTX and Patients 2 and 3 received further courses when symptoms returned and B-cells repopulated. Patient 3 did not receive RTX until 12 months from onset of symptoms. Patient 1 was not able to have further RTX treatments due to an allergic reaction when receiving the second dose. RTX treatment resulted in sustained remission and full recovery of anterior pituitary function in Patients 1 and 2 with complete resolution of pituitary enlargement. By contrast, Patient 3 only showed symptomatic response following RTX treatment, but pituitary enlargement and hypofunction persisted.ConclusionRTX treatment for IgG4-related hypophysitis resulted in sustained remission in two patients treated early in the disease process, but only achieved partial response in a patient with chronic disease suggesting that early therapeutic intervention may be crucial to avoid irreversible changes.
McAdoo S, Farrah TE, Prendecki M, et al., 2021, Glucocorticoid-free treatment of severe ANCA-associated vasculitis, Nephrology Dialysis Transplantation, Vol: 36, Pages: 739-742, ISSN: 0931-0509
Farrah TE, Prendecki M, Hunter RW, et al., 2021, Glucocorticoid-free treatment of severe ANCA-associated vasculitis., Nephrol Dial Transplant, Vol: 36, Pages: 739-742
Pokidysheva EN, Seeger H, Pedchenko V, et al., 2021, Collagen IVα345 dysfunction in glomerular basement membrane diseases. I. Discovery of a COL4A3 variant in familial Goodpasture's and Alport diseases, Journal of Biological Chemistry, Vol: 296, ISSN: 0021-9258
Diseases of the glomerular basement membrane (GBM), such as Goodpasture's disease (GP) and Alport syndrome (AS), are a major cause of chronic kidney failure and an unmet medical need. Collagen IVα345 is an important architectural element of the GBM that was discovered in previous research on GP and AS. How this collagen enables GBM to function as a permselective filter and how structural defects cause renal failure remain an enigma. We found a distinctive genetic variant of collagen IVα345 in both a familial GP case and four AS kindreds that provided insights into these mechanisms. The variant is an 8-residue appendage at the C-terminus of the α3 subunit of the α345 hexamer. A knock-in mouse harboring the variant displayed GBM abnormalities and proteinuria. This pathology phenocopied AS, which pinpointed the α345 hexamer as a focal point in GBM function and dysfunction. Crystallography and assembly studies revealed underlying hexamer mechanisms, as described in Companion Papers II and III. Bioactive sites on the hexamer surface were identified where pathogenic pathways of GP and AS converge, and, potentially, that of diabetic nephropathy (DN). We conclude that the hexamer functions include signaling and organizing macromolecular complexes, which enable GBM assembly and function. Therapeutic modulation or replacement of α345 hexamer could therefore be a potential treatment for GBM diseases, and this knock-in mouse model is suitable for developing gene therapies.
Nikolopoulou A, Teixeira C, Cook H, et al., 2021, Membranous nephropathy associated with viral infection, Clinical Kidney Journal, Vol: 14, Pages: 876-883, ISSN: 2048-8505
BackgroundMembranous nephropathy (MN) can be associated with hepatitis infection and less commonly with human immunodeficiency virus (HIV) infection. The significance of anti-phospholipase A2 receptor (PLA2R) and anti-thrombospondin type 1 domain-containing 7A (THSD7A) antibodies in this setting is unclear.MethodsWe describe the clinical, histopathological and outcome data of 19 patients with MN and hepatitis B virus (HBV), hepatitis C virus (HCV) or HIV infection identified through our renal biopsy database and the association with anti-PLA2R antibodies and anti-THSD7A antibodies.ResultsThe cohort consisted of 19 patients, 8 male and 11 female, with a median age of 42 years (range 23–74). HBV infection was found in six cases, HCV in four and HIV in nine (two HIV patients had HBV co-infection and one HCV co-infection). PLA2R staining on biopsy was positive in 10/19 patients: 4 with HBV-MN, 3 with HCV-MN and 3 with HIV-MN and circulating anti-PLA2R antibodies were detected in 7/10 cases. THSD7A staining on biopsy was positive in three PLA2R-negative cases, one with HBV-MN and two with HIV-MN. Mean proteinuria was higher in the PLA2R-positive group and the median urinary protein:creatinine ratio (uPCR) was 963 mg/mmol (range 22–2406) compared with the PLA2R-negative group [median uPCR 548 mg/mmol (range 65–1898); P = 0.18 Mann–Whitney]. Spontaneous remission occurred in 6/19 patients and after-treatment remission occurred in 7/11 patients. Renal function was preserved in all but two patients who required haemodialysis 2 and 11 years from diagnosis.ConclusionsWe describe a cohort of patients with MN associated with viral infection, including rare cases of HIV-MN with PLA2R and THSD7A positivity. The mechanism of coincidental or viral-related MN needs to be investigated further.
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