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Cook HT, 2018, Evolving complexity of complement-related diseases: C3 glomerulopathy and atypical haemolytic uremic syndrome, Current Opinion in Nephrology and Hypertension, Vol: 27, Pages: 165-170, ISSN: 1535-3842
PURPOSE OF REVIEW: The current review will discuss recent advances in our understanding of the pathology of C3 glomerulopathy and atypical haemolytic uremic syndrome (aHUS). RECENT FINDINGS: C3 glomerulopathy and aHUS are associated with abnormalities of control of the alternative pathway of complement. Recent articles have provided new insights into the classification of C3 glomerulopathy and its relationship to idiopathic immune complex-mediated glomerulonephritis. They suggest that there may be considerable overlap in pathogenesis between these entities and have indicated novel ways in which classification may be improved. There is increasing evidence that monoclonal gammopathy may cause C3 glomerulopathy or aHUS in older patients and emerging evidence that treatment of the underlying plasma cell clone may ameliorate the kidney disease. SUMMARY: Recent work has provided new insights into the causes of C3 glomerulopathy and aHUS, and the mechanism by which complement is dysregulated. This is of particular importance with the advent of new therapeutic agents which can specifically target different parts of the complement cascade.
Wilson H, Turner-Stokes T, Griffith M, et al., 2018, Twenty years of lupus nephritis management - evaluation of a multi ethnic patient cohort to identify factors affecting outcome, 55th Congress of the European-Renal-Association (ERA) and European-Dialysis-and-Transplantation-Association (EDTA), Publisher: Oxford University Press (OUP), ISSN: 0931-0509
Kocinsky H, Kelleher C, Apelian D, et al., 2018, FACTOR D INHIBITION WITH ACH-4471 TO REDUCE COMPLEMENT ALTERNATIVE PATHWAY HYPERACTIVITY AND PROTEINURIA IN C3 GLOMERULOPATHY: PRELIMINARY PROOF OF CONCEPT DATA, 55th Congress of the European-Renal-Association (ERA) and European-Dialysis-and-Transplantation-Association (EDTA), Publisher: OXFORD UNIV PRESS, Pages: 322-322, ISSN: 0931-0509
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Bajema IM, Wilhelmus S, Alpers CE, et al., 2018, Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices, Kidney International, Vol: 93, Pages: 789-796, ISSN: 0085-2538
We present a consensus report pertaining to the improved clarity of definitions and classification of glomerular lesions in lupus nephritis that derived from a meeting of 18 members of an international nephropathology working group in Leiden, Netherlands, in 2016. Here we report detailed recommendations on issues for which we can propose adjustments based on existing evidence and current consensus opinion (phase 1). New definitions are provided for mesangial hypercellularity and for cellular, fibrocellular, and fibrous crescents. The term "endocapillary proliferation" is eliminated and the definition of endocapillary hypercellularity considered in some detail. We also eliminate the class IV-S and IV-G subdivisions of class IV lupus nephritis. The active and chronic designations for class III/IV lesions are replaced by a proposal for activity and chronicity indices that should be applied to all classes. In the activity index, we include fibrinoid necrosis as a specific descriptor. We also make recommendations on issues for which there are limited data at present and that can best be addressed in future studies (phase 2). We propose to proceed to these investigations, with clinicopathologic studies and tests of interobserver reproducibility to evaluate the applications of the proposed definitions and to classify lupus nephritis lesions.
Hill NR, Cook T, Pusey C, et al., 2018, RIPK3-deficient mice were not protected from nephrotoxic nephritis, BMC Nephrology, Vol: 19, ISSN: 1471-2369
Background/Aims: Necrotizing glomerular lesions are a feature of severe glomerulonephritis. Unlike apoptosis, cellular necrosis has the potential to release damage-associated proteins into the microenvironment, thereby potentiating inflammation. Until recently necrosis was thought to be an unregulated cellular response to injury. However, recent evidence suggests that under certain circumstances receptor mediated necrosis occurs in response to death ligand signalling, one form of which is termed necroptosis. RIPK3, a receptor interacting protein, is a limiting step in the intracellular signalling pathway of necroptosis. A non-redundant role for RIPK3 has been implicated in mouse models of renal ischaemia reperfusion injury and toxic renal injury. The aim of this study was to investigate the role of RIPK3 in nephrotoxic nephritis (NTN), a model of immune complex glomerulonephritis in mice. Methods: We induced NTN in RIPK3-/- and WT mice, comparing histology and renal function in both groups. Results: There was no improvement in urinary albumin creatinine ratio, serum urea, glomerular thrombosis or glomerular macrophage infiltration in the RIPK3-/- mice compared to WT. There was also no difference in number of apoptotic cells in glomeruli as measured by TUNEL staining between the RIPK3-/- and WT mice. Conclusion: The data suggests that RIPK3 is not on a critical pathway in the pathogenesis of nephrotoxic nephritis.
Medjeral-Thomas NR, Troldborg A, Constantinou N, et al., 2018, Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin-Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H-Related Protein-5 (FHR5) Deposition, KIDNEY INTERNATIONAL REPORTS, Vol: 3, Pages: 426-438, ISSN: 2468-0249
IntroductionIgA nephropathy (IgAN) is characterized by glomerular deposition of galactose-deficient IgA1 and complement proteins and leads to renal impairment. Complement deposition through the alternative and lectin activation pathways is associated with renal injury.MethodsTo elucidate the contribution of the lectin pathway to IgAN, we measured the 11 plasma lectin pathway components in a well-characterized cohort of patients with IgAN.ResultsM-ficolin, L-ficolin, mannan-binding lectin (MBL)–associated serine protease (MASP)-1 and MBL-associated protein (MAp) 19 were increased, whereas plasma MASP-3 levels were decreased in patients with IgAN compared with healthy controls. Progressive disease was associated with low plasma MASP-3 levels and increased glomerular staining for C3b/iC3b/C3c, C3d, C4d, C5b-9, and factor H–related protein 5 (FHR5). Glomerular FHR5 deposition positively correlated with glomerular C3b/iC3b/C3c, C3d, and C5b-9 deposition, but not with glomerular C4d. These observations, together with the finding that glomerular factor H (fH) deposition was reduced in progressive disease, are consistent with a role for fH deregulation by FHR5 in renal injury in IgAN.ConclusionOur data indicate that circulating MASP-3 levels could be used as a biomarker of disease severity in IgAN and that glomerular staining for FHR5 could both indicate alternative complement pathway activation and be a tissue marker of disease severity.
Hamaoui K, Gowers S, Sandhu B, et al., 2018, Development of pancreatic machine perfusion: translational steps from porcine to human models, JOURNAL OF SURGICAL RESEARCH, Vol: 223, Pages: 263-274, ISSN: 0022-4804
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Cook HT, Pickering MC, 2017, Clusters not classifications: making sense of complement-mediated kidney injury, Journal of the American Society of Nephrology, Vol: 29, Pages: 9-12, ISSN: 1046-6673
Wilson HR, Gilmore A, Medjeral-Thomas NR, et al., 2017, The spectrum of complement C9 staining in lupus nephritis, 16th European Meeting on Complement in Human Disease (EMCHD), Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 179-179, ISSN: 0161-5890
Turner S, Yeung KT, Moser S, et al., 2017, ULTRASOUND-GUIDED ALLOGRAFT PANCREAS BIOPSY: SAFETY AND DIAGNOSTIC USE, Publisher: WILEY, Pages: 141-141, ISSN: 0934-0874
Medjeral-Thomas NR, Troldborg A, Lomax-Browne H, et al., 2017, Plasma levels of lectin pathway components in IgA nephropathy, 16th European Meeting on Complement in Human Disease (EMCHD), Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 178-178, ISSN: 0161-5890
Lomax HJ, Medjeral-Thomas NR, Cook HT, et al., 2017, Natural history study of C3 glomerulopathy, 16th European Meeting on Complement in Human Disease (EMCHD), Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 176-176, ISSN: 0161-5890
Turner-Stokes T, Wilson HR, Morreale M, et al., 2017, Positive antineutrophil cytoplasmic antibodyserology in patients with lupus nephritis isassociated with distinct histopathologic featureson renal biopsy, Kidney International, Vol: 92, Pages: 1223-1231, ISSN: 1523-1755
Class IV-S lupus nephritis (LN) is often associated with more necrosis and fewer subendothelial immune deposits compared to class IV-G LN, suggestive of the necrotising glomerular inflammation found in ANCA-associated vasculitis. ANCA are present in a significant proportion of patients with LN. The aim of this study was to determine whether ANCA are associated with distinct clinical and histopathological features of LN. 32 ANCA positive biopsies were compared to 222 ANCA negative biopsies from patients with LN. The majority of ANCA positive patients had anti-MPO antibodies (82%). Class IV-S LN and glomerular necrosis were more common (36% vs. 16%, p=0.0253 and 35% vs. 15%, p=0.025 respectively) and isolated Class V LN less common (10% vs. 29%, p=0.0282) in the ANCA positive group. ANCA positive patients had higher dsDNA titres (335u/ml vs. 52u/ml, p=0.00007), lower serum C4 concentration (0.125g/L vs. 0.15g/L, p=0.027) and higher serum creatinine (130µmol/L vs. 84µmol/L, p=0.047) at time of biopsy. Hence ANCA appear to influence the histological pattern of LN and are associated with worse baseline renal function and more active lupus serology. There was no significant difference in outcome between groups when matched for severity of disease and treatment using propensity scoring. Further studies are needed to examine whether ANCA in patients with LN have a pathogenic role and whether they are associated with worse renal outcomes or are simply a marker of more severe disease.
Medjeral-Thomas NR, Lomax-Browne HJ, Beckwith H, et al., 2017, Circulating complement factor H-related proteins 1 and 5 correlate with disease activity in IgA nephropathy, Kidney International, Vol: 92, Pages: 942-952, ISSN: 0085-2538
IgA nephropathy (IgAN) is a common cause of chronic kidney disease and end-stage renal failure, especially in young people. Due to a wide range of clinical outcomes and difficulty in predicting response to immunosuppression, we need to understand why and identify which patients with IgAN will develop progressive renal impairment. A deletion polymorphism affecting the genes encoding the complement factor H-related protein (FHR)-1 and FHR-3 is robustly associated with protection against IgAN. Some FHR proteins, including FHR-1 and FHR-5, antagonize the ability of complement factor H (fH), the major negative regulator of the complement alternative pathway, to inhibit complement activation on surfaces, a process termed fH deregulation. From a large cohort of patients, we demonstrated that plasma FHR-1 and the FHR-1/fH ratio were elevated in IgAN and associated with progressive disease. Plasma FHR-1 negatively correlated with eGFR but remained elevated in patients with IgAN with normal eGFR. Serum FHR5 was slightly elevated in IgAN but did not correlate with eGFR. Neither FHR5 levels nor the FHR-5/fH ratio was associated with progressive disease. However, higher serum FHR-5 levels were associated with a lack of response to immunosuppression, the presence of endocapillary hypercellularity, and histology scores of disease severity (the Oxford Classification MEST score). Thus, FHR-1 and FHR-5 have a role in IgAN disease progression.
Chen T, Rotival M, Behmoaras JV, et al., 2017, Identification of ceruloplasmin as a gene that affects susceptibility to glomerulonephritis through macrophage function, Genetics, Vol: 206, Pages: 1139-1151, ISSN: 1943-2631
Crescentic glomerulonephritis (Crgn) is a complex disorder where macrophage activity and infiltration are significant effector causes. In previous linkage studies using the uniquely susceptible Wistar Kyoto (WKY) rat strain, we have identified multiple crescentic glomerulonephritis QTL (Crgn) and positionally cloned genes underlying Crgn1 and Crgn2, which accounted for 40% of total variance in glomerular inflammation. Here, we have generated a backcross (BC) population (n = 166) where Crgn1 and Crgn2 were genetically fixed and found significant linkage to glomerular crescents on chromosome 2 (Crgn8, LOD = 3.8). Fine mapping analysis by integration with genome-wide expression QTLs (eQTLs) from the same BC population identified ceruloplasmin (Cp) as a positional eQTL in macrophages but not in serum. Liquid chromatography-tandem mass spectrometry confirmed Cp as a protein QTL in rat macrophages. WKY macrophages overexpress Cp and its downregulation by RNA interference decreases markers of glomerular proinflammatory macrophage activation. Similarly, short incubation with Cp results in a strain-dependent macrophage polarization in the rat. These results suggest that genetically determined Cp levels can alter susceptibility to Crgn through macrophage function and propose a new role for Cp in early macrophage activation.
Stratigou V, Doyle, Carlucci F, et al., 2017, Altered expression of signalling lymphocyte activation molecule (SLAM) receptors in T cells from lupus nephritis patients - a potential biomarker of disease activity., Rheumatology, Vol: 56, Pages: 1206-1216, ISSN: 1462-0332
Objectives. The aim was to investigate whether the signalling lymphocyte activation molecule (SLAM) signalling pathways contribute to LN and whether SLAM receptors could be valuable biomarkers of disease activity.Methods. Peripheral blood mononuclear cells from 30National Research Ethics Service SLE patients with biopsy-proven LN were analysed by flow cytometry. Clinical measures of disease activity were assessed. The expression of the SLAM family receptors on T-cell subpopulations [CD4, CD8 and double negative (DN) T cells] was measured and compared between lupus patients with active renal disease and those in remission.Results. The frequency of CD8 T cells expressing SLAMF3, SLAMF5 and SLAMF7 was significantly lower in LN patients who were in remission. In contrast, these subsets were similar in patients with active renal disease and in healthy individuals. Patients with active nephritis had an increased percentage of circulating monocytes, consistent with a potential role played by these cells in glomerular inflammation. Changes in the frequency of DN T cells positive for SLAMF2, SLAMF4 and SLAMF7 were observed in lupus patients irrespective of the disease activity. We detected alterations in the cellular expression of the SLAM family receptors, but these changes were less obvious and did not reveal any specific pattern. The percentage of DN T cells expressing SLAMF6 could predict the clinical response to B-cell depletion in patients with LN.Conclusion. Our study demonstrates altered expression of the SLAM family receptors in SLE T lymphocytes. This is consistent with the importance of the SLAM-associated pathways in lupus pathogenesis.
Dominy K, Willicombe M, Al Johani T, et al., 2017, Validation of <i>CYP4F11</i> as a Marker of Accommodation in Biopsies from Recipients of an ABO-Incompatible Renal Transplant, American Transplant Congress, Publisher: WILEY, Pages: 451-452, ISSN: 1600-6135
Dominy K, Willicombe M, Al Johani T, et al., 2017, Assessment of C4d Positive Biopsies with No Histological Evidence of Inflammation Using Nanostring nCounter Technology, American Transplant Congress, Publisher: WILEY, Pages: 721-722, ISSN: 1600-6135
Chen T, Rasch L, Al Johani T, et al., 2017, The Immunophenotype of Peritubular Capillaritis in Renal Transplant Biopsies, American Transplant Congress, Publisher: WILEY, Pages: 722-723, ISSN: 1600-6135
Trimarchi H, Barratt J, Cattran DC, et al., 2017, Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group, KIDNEY INTERNATIONAL, Vol: 91, Pages: 1014-1021, ISSN: 0085-2538
Since the Oxford Classification of IgA nephropathy (IgAN) was published in 2009, MEST scores have been increasingly used in clinical practice. Further retrospective cohort studies have confirmed that in biopsy specimens with a minimum of 8 glomeruli, mesangial hypercellularity (M), segmental sclerosis (S), and interstitial fibrosis/tubular atrophy (T) lesions predict clinical outcome. In a larger, more broadly based cohort than in the original Oxford study, crescents (C) are predictive of outcome, and we now recommend that C be added to the MEST score, and biopsy reporting should provide a MEST-C score. Inconsistencies in the reporting of M and endocapillary cellularity (E) lesions have been reported, so a web-based educational tool to assist pathologists has been developed. A large study showed E lesions are predictive of outcome in children and adults, but only in those without immunosuppression. A review of S lesions suggests there may be clinical utility in the subclassification of segmental sclerosis, identifying those cases with evidence of podocyte damage. It has now been shown that combining the MEST score with clinical data at biopsy provides the same predictive power as monitoring clinical data for 2 years; this requires further evaluation to assess earlier effective treatment intervention. The IgAN Classification Working Group has established a well-characterized dataset from a large cohort of adults and children with IgAN that will provide a substrate for further studies to refine risk prediction and clinical utility, including the MEST-C score and other factors.
Cook HT, 2017, C3 glomerulopathy., F1000Research, Vol: 6, ISSN: 2046-1402
C3 glomerulopathy is a recently defined entity that encompasses a group of kidney diseases caused by abnormal control of complement activation with deposition of complement component C3 in glomeruli leading to variable glomerular inflammation. Before the recognition of the unique pathogenesis of these cases, they were variably classified according to their morphological features. C3 glomerulopathy accounts for roughly 1% of all renal biopsies. Clear definition of this entity has allowed a better understanding of its pathogenesis and clinical course and is likely to lead to the design of rational therapies over the next few years.
McAdoo SP, Gopaluni S, Medjeral-Thomas N, et al., 2017, Long-term follow-up of a combined rituximab and low-dose cyclophosphamide regimen for remission induction in renal anca-associated vasculitis, Rheumatology, Vol: 56, Pages: 153-153, ISSN: 1462-0324
Haas M, Verhave JC, Liu ZH, et al., 2017, A multicenter study of the predictive value of crescents in IgA nephropathy, Journal of the American Society of Nephrology, Vol: 28, Pages: 691-701, ISSN: 1533-3450
The Oxford Classification of IgA nephropathy does not account for glomerular crescents. However, studies that reported no independent predictive role of crescents on renal outcomes excluded individuals with severe renal insufficiency. In a large IgA nephropathy cohort pooled from four retrospective studies, we addressed crescents as a predictor of renal outcomes and determined whether the fraction of crescent-containing glomeruli associates with survival from either a ≥50% decline in eGFR or ESRD (combined event) adjusting for covariates used in the original Oxford study. The 3096 subjects studied had an initial mean±SD eGFR of 78±29 ml/min per 1.73 m(2) and median (interquartile range) proteinuria of 1.2 (0.7-2.3) g/d, and 36% of subjects had cellular or fibrocellular crescents. Overall, crescents predicted a higher risk of a combined event, although this remained significant only in patients not receiving immunosuppression. Having crescents in at least one sixth or one fourth of glomeruli associated with a hazard ratio (95% confidence interval) for a combined event of 1.63 (1.10 to 2.43) or 2.29 (1.35 to 3.91), respectively, in all individuals. Furthermore, having crescents in at least one fourth of glomeruli independently associated with a combined event in patients receiving and not receiving immunosuppression. We propose adding the following crescent scores to the Oxford Classification: C0 (no crescents); C1 (crescents in less than one fourth of glomeruli), identifying patients at increased risk of poor outcome without immunosuppression; and C2 (crescents in over one fourth of glomeruli), identifying patients at even greater risk of progression, even with immunosuppression.
Beckwith H, Medjeral-Thomas N, Galliford J, et al., 2017, Mycophenolate mofetil therapy in immunoglobulin A nephropathy: histological changes after treatment, Nephrology Dialysis Transplantation, Vol: 32, Pages: i123-i128, ISSN: 0931-0509
BackgroundEndocapillary hypercellularity independently predicts renal outcome in immunoglobulin A nephropathy (IgAN). Mycophenolate mofetil (MMF) treatment is offered to patients presenting to the Imperial College Renal and Transplant Centre with IgAN and histological evidence of endocapillary hypercellularity. Clinical trials of MMF in IgAN have been inconclusive and have been limited by a lack of specific histological inclusion and exclusion criteria when recruiting patients. Evidence of histological improvement following MMF treatment would support its therapeutic use. We therefore reviewed histological changes after MMF therapy in a cohort of IgAN patients.MethodEighteen IgAN patients with native renal biopsies before and after repeated MMF treatment were identified. Patients were excluded if they had received any other immunosuppressive therapy, including corticosteroids. On the basis of the Oxford Classification of IgAN, we reviewed histological changes after MMF treatment.ResultsNine patients (50%) were male. At diagnostic renal biopsy, the median age was 35 years [interquartile range (IQR) 30–41], serum creatinine was 97 µmol/L (IQR 79–153) and urine protein creatinine ratio (UPCR) was 146 mg/mmol (IQR 98–212). The median time between biopsies was 24 months (range 9–41). Following MMF treatment, repeat biopsy demonstrated statistically significant improvement in the mean percentage of glomeruli showing endocapillary hypercellularity and cellular/fibrocellular crescents. There was no change in mesangial hypercellularity, segmental sclerosis or tubular atrophy scores. Mesangial IgA deposition was also significantly reduced. Histopathological improvement persisted after the cessation of MMF therapy, suggesting that 2 years of treatment is adequate for benefit. The median serum creatinine remained stable at 3 years follow-up at 104 µmol/L (IQR 79–147).ConclusionMMF treatment is associated with histopathological improveme
Lomax-Browne HJ, Visconti A, Pusey CD, et al., 2017, IgA1 glycosylation is heritable in healthy twins, Journal of the American Society of Nephrology, Vol: 28, Pages: 64-68, ISSN: 1533-3450
IgA Nephropathy (IgAN) is the most common form of primary glomerulonephritis and an important cause of kidney failure. Characteristically, IgAN patients have increased serum levels of under-galactosylated IgA1 (gd-IgA1). We assessed the degree to which serum gd-IgA1 levels are genetically determined in healthy individuals. Serum IgA and gd-IgA1 level were determined by ELISA in a sample of 148 healthy female twins including 27 monozygotic and 47 dizygotic pairs. Using the classical twin model, the heritability of serum gd-IgA1 and IgA levels were 80% (95% CI: 66-89%) and 46% (95% CI: 15-69%) respectively. These data indicate that serum gd-IgA1 levels are highly heritable. Elucidating the genetic basis of this heritability will be important in understanding the pathogenesis of IgAN.
Prendecki M, Tanna A, Salama AD, et al., 2016, Long-term outcome in biopsy-proven acute interstitial nephritis treated with steroids., Clinical Kidney Journal, Vol: 10, Pages: 233-239, ISSN: 2048-8505
Background: There are no prospective randomized controlled trials describing the outcome of acute interstitial nephritis (AIN) treated with steroids, and retrospective studies are limited. Methods: We identified adult patients with a diagnosis of AIN without glomerular pathology over a 14-year period. Treated patients all received oral prednisolone and three also recieved IV methylprednisolone. Data were collected retrospectively on estimated glomerular filtration rate (eGFR), change in eGFR from time of biopsy, dependence on renal replacement therapy (RRT) and mortality, and outcomes were analysed according to the treatment prescribed. Results: A total of 187 eligible patients with AIN were identified and 158 were treated with steroids. There was no difference in median eGFR or dependence on RRT at the time of biopsy. Steroid-treated patients had significantly higher eGFR at all time points post-biopsy up to 24 months, when median eGFR was 43 mL/min in the steroid-treated group and 24 mL/min in the untreated group (P = 0.01). Fewer patients in the steroid-treated group were dialysis dependent by 6 months (3.2% versus 20.6%, P = 0.0022) and 24 months (5.1% versus 24.1%, P = 0.0019). Conclusions: This large retrospective study suggests a benefit of steroids in treatment of AIN with greater improvement in eGFR and fewer patients progressing to end-stage renal disease.
Goodship THJ, Cook HT, Fakhouri F, et al., 2016, Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference, Kidney International, Vol: 91, Pages: 539-551, ISSN: 0085-2538
In both atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) complement plays a primary role in disease pathogenesis. Herein we report the outcome of a 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference where key issues in the management of these 2 diseases were considered by a global panel of experts. Areas addressed included renal pathology, clinical phenotype and assessment, genetic drivers of disease, acquired drivers of disease, and treatment strategies. In order to help guide clinicians who are caring for such patients, recommendations for best treatment strategies were discussed at length, providing the evidence base underpinning current treatment options. Knowledge gaps were identified and a prioritized research agenda was proposed to resolve outstanding controversial issues.
Webster P, Webster LM, Cook HT, et al., 2016, A multicenter cohort study of histologic findings and long-term outcomes of kidney disease in women who have been pregnant, Clinical Journal of the American Society of Nephrology, Vol: 12, Pages: 408-416, ISSN: 1555-905X
BACKGROUND AND OBJECTIVES: For many women pregnancy is the first contact with health services, thus providing an opportunity to identify renal disease. This study compares causes and long-term renal outcomes of biopsy-proven renal disease identified during pregnancy or within 1 year postpartum, with nonpregnant women. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Native renal biopsies (1997-2012), in women of childbearing age (16 to <50 years), from 21 hospitals were studied. The pregnancy-related diagnosis group included those women with abnormal urinalysis/raised creatinine identified during pregnancy or within 1 year postpartum. Pregnancy-related and control biopsies were matched for age and ethnicity (black versus nonblack). RESULTS: One hundred and seventy-three pregnancy-related biopsies (19 antenatal, 154 postpregnancy) were identified and matched with 1000 controls. FSGS was more common in pregnancy-related biopsies (32.4%) than controls (9.7%) (P<0.001) but there were no differences in Columbia classification. Women with a pregnancy-related diagnosis were younger (32.1 versus 34.2 years; P=0.004) and more likely to be black (26.0% versus 13.3%; P<0.001) than controls, although there were no differences in ethnicities in women with FSGS. The pregnancy-related group (excluding antenatal biopsies) was more likely to have a decline in Chronic Kidney Disease Epidemiology Collaboration eGFR in the follow-up period than the control group (odds ratio, 1.67; 95% confidence interval, 1.03 to 2.71; P=0.04), and this decline appeared to be more rapid (-1.33 versus -0.56 ml/min per 1.73 m(2) per year, respectively; P=0.045). However, there were no differences between groups in those who required RRT or who died. CONCLUSIONS: Pregnancy is an opportunity to detect kidney disease. FSGS is more common in women who have been pregnant than in controls, and disease identified in pregnancy or within 1 year postpartum is more likely to show a subsequent decline in
Bellur SS, Lepeytre F, Vorobyeva O, et al., 2016, Evidence from the Oxford Classification cohort supports the clinical value of subclassification of focal segmental glomerulosclerosis in IgA nephropathy, Kidney International, Vol: 91, Pages: 235-243, ISSN: 0085-2538
Focal segmental glomerulosclerosis (FSGS) is a common finding in IgA nephropathy (IgAN). Here we assessed FSGS lesions in the Oxford Classification patient cohort and correlated histology with clinical presentation and outcome to determine whether subclassification of the S score in IgAN is reproducible and of clinical value. Our subclassification of lesions in 137 individuals with segmental glomerulosclerosis or adhesion (S1) identified 38% with podocyte hypertrophy, 10% with hyalinosis, 9% with resorption droplets within podocytes, 7% with tip lesions, 3% with perihilar sclerosis, and 2% with endocapillary foam cells. Reproducibility was good or excellent for tip lesions, hyalinosis, and perihilar sclerosis; moderate for podocyte hypertrophy; and poor for resorption droplets, adhesion only, and endocapillary foam cells. Podocyte hypertrophy and tip lesions were strongly associated with greater initial proteinuria. During follow-up of patients without immunosuppression, those with these features had more rapid renal function decline and worse survival from a combined event compared to S1 patients without such features and those without FSGS. Also in individuals with podocyte hypertrophy or tip lesions, immunosuppressive therapy was associated with better renal survival. In IgA nephropathy, the presence of podocyte hypertrophy or tip lesions, markers of podocyte injury, were reproducible. These features are strongly associated with proteinuria and, in untreated patients, carry a worse prognosis. Thus, our findings support reporting podocytopathic features alongside the S score of the Oxford Classification.
Hamaoui K, Gowers S, Boutelle M, et al., 2016, Organ pre-treatment with cytotopic endothelial localising peptides to ameliorate microvascular thrombosis & perfusion deficits in ex-vivo renal haemo-reperfusion models, Transplantation, Vol: 100, Pages: e128-e139, ISSN: 1534-6080
Background: Hypothermic machine organ perfusion (HMP) offers opportunity to manipulate grafts with pharmacological agents prior to transplantation. Pre-treating organs with novel cytotopic anti-coagulant peptides that localise to endothelial cell membranes could ameliorate microvascular thrombotic sequelae post-transplantation. We describe experiments testing Thrombalexin (TLN), a novel cell binding thrombin-inhibitor, using porcine and unused human kidneys in a series of ex-vivo normothermic haemo-reperfusion models. Methods: 38 porcine kidneys were utilised. Control kidneys underwent pretreatment via HMP with either unmodified perfusion solution (n=15) or solution with Inactive-TLN (absent anticoagulant effect, n=4). Test kidneys were perfused with TLN treated solution (n=19). All kidneys then underwent haemo-reperfusion. Two unused human kidneys underwent a similar protocol.Results: HMP pretreatment facilitated delivery and tethering of TLN in the organ microvasculature. Haemo-reperfusion challenge demonstrated improved perfusion in TLN-treated kidneys compared to controls: 26.4% superior flow (30.6 vs.23.1 ml/min/100g,p=0.019) and 28.9% higher perfusion flow indices (0.43 vs.0.32 ml/min/100g/mmHg,p=0.049). Orthogonal polarisation spectral imaging demonstrated superior microvascular capillary perfusion in TLN-treated organs vs. controls (9.1 vs. 2.8pl/s/mm2,p=0.021). Rapid-sampling microdialysis for cortical [lactate] as a marker of tissue ischaemia/metabolism detected lower levels in TLN-treated kidneys. Perfusate analysis demonstrated reduced fibrin generation in TLN-treated kidneys correlating with perfusion data. Conclusion: Our data suggest HMP graft pretreatment with cytotopic anticoagulants is feasible and ameliorates perfusion deficits seen in ex-vivo haemo-reperfusion models. There is potential for further development and application of this translational strategy to deliver locally-active anti-coagulants directly within grafts and decrease microvascular
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