bluuebunny/crossref_metadata_2025 huggingface dataset:
P0356QUANTITATIVE ASSESSMENT OF GALNAC NUMBER IN THE HINGE REGION OF IGA1 IN IGA NEPHROPATHY WITH CRESCENTS FORMING
Authors: Yu Guizhen , Zhang Yong , Xie Xinfang , Meng Bo , Ying Wantao , Lv Jicheng , Zhang Hong
Published: June 2020

Background and Aims

Aberrant IgA1 O-linked glycosylation of IgA1 hinge region (HR) has been shown playing an important role in the pathogenesis of IgA nephropathy (IgAN). Serum levels of galactose-deficient IgA1 (Gd-IgA1) was associated with the development and progression in IgAN, however variations in the composition of IgA1 HR glycoforms are unknown. In this study we aim to quantitative assessment of GalNAc number in the hinge region of IgA1 in IgAN with crescents forming using mass spectrometry.

Method

Plasma polymeric IgA1 (pIgA1) was purified from a discovery cohort including crescentic IgAN (n=11) non-crescentic IgAN (n=10) and healthy controls (HC, n=10) and a validation cohort (crescentic IgAN, n=10; non-crescentic IgAN, n=10 and healthy controls, n=11). After denaturation, reduction, alkylation and trypsin digestion, liquid chromatography-high-resolution mass spectrometry (LC-MS) was used to analyse the IgA1 HR glycans. The intensity of the identified IgA1 O-glycopeptide was calculated and expressed as the relative abundance for each glycopeptide. The molecular weight (MW) of intact O-glycopeptide was calculated as the formula following:

MW = HR + x GalNAc + y Gal + z NeuAc + H+

(x, y and z represent the number of GalNAc, galactose and NeuAc which bind to one HR in IgA1 O-linked glycopeptides respectively)

Glycopeptide content ratio = (glycopeptide peak intensity/ total glycopeptide intensity) ×100%.

Results

In the discovery cohort population, the level of Gd-IgA1 was highest in patients with crescentic IgAN, middle in patients with non-crescentic IgAN and lowest in healthy controls (347.69±57.89 U/ml vs 336.32±38.44 U/ml vs 330.14±33.22 U/ml), albeit that didn’t reach the statistical significance. There were significantly difference in GalNAc number of IgA1 HR among patients with IgAN and healthy controls. Overall the numbers of GalNAc bound to one HR was much lower in the patients than healthy controls. As shown in the Figure 1, the proportion of GalNAc 3, defined as O-glycans that were bound to one HR at 3 sites, were highest in patients with crescentic IgAN, then the non-crescentic IgAN and lowest in the healthy controls (9.92%±3.37% vs 6.65%±1.53% vs 4.05%±1.24%; p-value for the trend<0.001). Similar results were observed in GalNAc 4 (45.91%±4.75% vs 41.13%±2.95% vs 40.98%±2.95%; P=0.004. However regarding the GalNAc 5 and GalNAc 6, crescentic IgAN was lowest, then non-crescentic IgAN and highest in the healthy control (GalNAc 5: 45.17%±5.46% vs 46.90%±2.78% vs 48.05%±3.02%, P=0.001 GalNAc 6:1.62%±1.60% vs 3.95%±1.92% vs 5.39%±2.38%; P<0.001). These results were consistent in the validation cohort (Figure 1).

Conclusion

GalNAc numbers in IgA1 HR was lower in patients with IgAN especially in crescentic IgAN. These results suggest that the O-glycans of IgA1 were associated with the severe phenotype in IgA nephropathy.
P0358HYDROXYCHLOROQUINE PREVENTS ANTI-GBM GLOMERULONEPHRITIS IN RATS
Authors: Torigoe Miki , Obata Yoko , Inoue Hiro , Torigoe Kenta , Kinoshita Akira , Koji Takehiko , Nishino Tomoya
Published: June 2020

Background and Aims

Anti-glomerular basement membrane (GBM) glomerulonephritis (GN), characterized by glomerular crescent formation, requires early treatment because of poor prognosis. Hydroxychloroquine (HCQ) is a well-known antimalarial drug. In addition, it has immunomodulatory, anti-inflammatory, and autophagy inhibitory effects and its recognized in the treatment of autoimmune disease such as SLE. However, its effect for anti-GBM GN is unknown. In this study, we investigated the effect of HCQ against anti-GBM GN in rats.

Method

7 week old male, WKY rats were induced by the administration of anti-GBM serum (50μg/rat). We administered either HCQ (50mg/kg) or vehicle (Phosphate-buffered saline) from day 0 to day 7 after the induction of nephritis. Renal function was assessed by measuring serum creatinine, proteinuria, hematuria. Urine was collected for 24 hours on day 1, 3, 5, and 7. Rats were sacrificed on day 7 after induction of anti-GBM GN. Renal histological changes were assessed by PAS staining, and Masson trichrome stain, and macrophage was assessed by ED-1 stain. Mitogen-Activated Protein Kinase (MAPK) was evaluated by western blotting (WB) and inflammatory cytokines were evaluated by ELISA using urine.

Results

HCQ treatment suppressed renal function decline. Histologically, extracellular and intracellular cells were increased from day 1, fibrinoid necrosis and ED-1 positive cells were observed from day 3. Rats with anti-GBM GN had high levels of interferon-α, interleukin-6, monocyte chemotactic protein-1, and tumor necrosis factor-α. These changes were significantly suppressed by HCQ. In addition, HCQ suppressed phosphorylation of JNK/p38 MAPK.

Conclusion

Our study showed that HCQ could attenuate anti-GBM GN and have an anti-inflammatory effect by inhibiting JNK/p38 MAPK activation. HCQ may have therapeutic potential in anti-GBM GN.
P0373MEPOLIZUMAB THERAPY FOR EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (EGPA) - ONE YEAR FOLLOW-UP STUDY USING ANTI-IL5 AS A STEROID SPARING THERAPEUTIC APPROACH
Authors: Egan Allyson , Sivasothy Pasupathy , Gore Robin , MartinezDel-Pero Marcos , Willcocks Lisa , Smith Rona , Burns Stella , Owen Caroline , Jones Rachel B , Jayne David
Published: June 2020

Background and Aims

EGPA is a small vessel vasculitis characterised by the presence of tissue eosinophilia, necrotising vasculitis and granulomatous inflammation1. Typically, a prodromal asthmatic phase, leads to an eosinophilic stage, which can evolve to include the presence of vasculitis with renal manifestations. In the recent randomised, placebo-controlled MIRRA trial for relapsing and refractory EGPA, adjuvant therapy with anti-IL5 mAB Mepolizumab [MEPO] at 300mg s/c monthly, accrued longer times in remission, reduced steroid exposure and reduced relapse rates2. The aim of our study was to analyse the response and outcome for EGPA patients who received 100mg s/c of MEPO monthly for a minimum of 52 weeks, with particular focus on the steroid minimisation benefits.

Method

This retrospective, descriptive study analysed 13 patients with EGPA, who received 100mg s/m monthly MEPO therapy under the eosinophilic asthma care-pathway. Time points of assessment included MEPO commencement [M0] and 12 [M12] months.

Results

One patient had MEPO switched to Rituximab to treat both EGPA and new onset rheumatoid arthritis

Conclusion

The relapsing nature of EGPA places a potential dependency of therapy on steroids for asthmatic and vasculitic flares. This underscores the importance of targeted pathway specific biologic therapy to minimise steroid exposure, prevent tissue damage and ensure early response to therapy. This study demonstrates that anti-IL5 serves as a favourable model with steroid minimisation, improvement in asthma control questionnaire, reduction in BVAS and eosinophil counts at the 100mg s/c dosage. ANCA positive serology normalised in all four patients, independent of subtype. Well tolerated, it demonstrated considerable clinical benefit, with 12 patients [92.3%] continuing anti-IL5 therapy beyond 12 months. Adjuvant therapy with conventional immunosuppressants was well tolerated and renal function was preserved.

ADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. J.C.Jenette, et al Revised International Chapel Hil Consensus Conference Nomenclature of Vasculitides. 65, 1–11 (2013).

2. Wechsler, M. E. et al. Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N. Engl. J. Med. 376, 1921–1932 (2017).
P0379BION-1301, A FULLY BLOCKING ANTIBODY TARGETING APRIL FOR THE TREATMENT OF IGA NEPHROPATHY: ASSESSMENT OF SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS IN LONG-TERM NONCLINICAL STUDIES
Authors: Kreijtz Joost , Van Zandvoort Peter , Van de Crommert Jos , Friesen Maarten , Lo Jeannette , Endsley Aaron , Lauriault Veronique , Mueller Thomas , Van Elsas Andrea
Published: June 2020

Background and Aims

IgA Nephropathy (IgAN) is a common form of glomerulonephritis and its pathogenesis is thought to consist of sequential pathogenic hits, including the production of auto-antigen galactose-deficient IgA1 (Gd-IgA1) and auto-antibody formation ultimately resulting in immune complex deposition, inflammation and functional deterioration of the kidney. Serum levels of APRIL (A PRoliferation Inducing Ligand, TNFSF13) and levels of Gd-IgA1 are correlated with severity of disease (Zhao et al, 2012). As a ligand for the receptors BCMA and TACI, APRIL is thought to regulate differentiation and proliferation of B cells and plasma cells and IgA class switching. BION-1301 is a humanized antibody neutralizing APRIL. In nonhuman primates, BION-1301 reduced serum levels of IgA, IgM, and IgG with no drug-related toxicity (Dulos J, et al. ASN Annual Meeting. 2018). Here we describe the nonclinical safety assessment of BION-1301, to support its continued clinical development for the treatment of IgA Nephropathy.

Method

A 14-week repeat-dose toxicity and toxicokinetic/pharmacodynamic (TK/PD) study in non-human primates (NHP) was performed by biweekly intravenous bolus (IV) administration of BION-1301 at three different dose levels. To support a potential change in route of administration, a 4-week repeat-dose NHP bridging study was conducted with weekly subcutaneous (SC) administration of BION-1301 at three different dose levels.

Results

In both the 14-week IV study and the 4-week SC study, BION-1301 was evaluated for safety, TK and PD. For TK and PD, BION-1301 levels, uncomplexed APRIL levels and immunoglobulin levels (IgA, IgG, IgM) were quantified in serum. Immunophenotyping was performed on peripheral blood to assess the impact of BION-1301 on the B cell compartment. In both studies BION-1301 was well tolerated with no test-article related findings. 14-week IV dosing as well as 4-week SC dosing of BION-1301 reduced serum APRIL levels as well as serum immunoglobulin levels.

Conclusion

Results of these nonclinical toxicity studies with toxicology, TK and PD endpoints demonstrate that BION-1301 is well tolerated for up to 14 weeks of dosing, corroborates pharmacodynamic proof-of-mechanism and support prolonged dosing and SC administration of BION-1301 in patients with IgA Nephropathy.
P0382“FALSE” POSITIVITY OF SERUM ANTI-PHOSPHOLIPASE A2 RECEPTOR ANTIBODY (ANTI-PLA2R AB) IN PATIENTS WITH NON MEMBRANOUS GLOMERULAR DISEASE
Authors: Mok Irene , Choo Jason
Published: June 2020

Background and Aims

Phospholipase A2 receptor (PLA2R) is the major target antigen in primary membranous nephropathy (PMN) and the detection of circulating autoantibodies to PLA2R (Anti-PLA2R Ab) is a major advance in understanding this disease. In this study, we aimed to determine if Anti-PLA2R Ab serves as a specific marker for PMN in our multi-ethnic Southeast Asian cohort.

Method

This was a prospective cohort study of all adults with glomerular disease undergoing biopsy between 1st January 2015 and 30th June 2018. Anti-PLA2R antibody levels were quantitatively determined by IgG ELISA (Euroimmun). Results are expressed as RU/ml. We considered a value of >20RU/ml to represent a positive result, value of <14RU/ml to be negative and values between 14-20 RU/ml to be indeterminate.

Results

Out of the cohort of 192 patients, there were 27 patients with Membranous Nephropathy (MN), with 12 PMN and 15 with secondary MN (SMN). Secondary causes were Hepatitis (1), Malignancy (1), Lupus (13). In our analyses, 10 (83.3%) PMN pts were positive for Anti-PLA2R Ab, with 7(58.3%) strongly positive with titres >200RU/ml and 2(16.7%) negative. For SMN, the majority, 12 out of 14 patients (85.7%) tested negative and the remaining 2 (7.7%) yielded values of indeterminate levels.

Of note, among the 165 patients with non membranous glomerular disease, there were 15 patients (9.1%) with indeterminate Anti-PLA2R Ab levels and 31 patients (18.9%) tested positive for Anti-PLA2R antibody, with levels >20 RU/ml. Of these 31 patients, the majority of the patients had low levels of Anti-PLA2R Ab of <50 RU/ml. However there were 5 patients who had considerably high levels of Anti-PLA2R Ab of >50 RU/ml and their characteristics are tabled below (Table 1)

Conclusion

Consistent with other published studies, positive Anti-PLA2R antibody levels were highly specific for PMN in our multi-ethnic Southeast Asian population and our centre has since been consistently using this test for differentiating between PMN and SMN. What is most striking in our study is that we have found high-titre Anti-PLA2R antibody positivity in non-MN patients, which has not been frequently reported in literature. The unifying feature amongst these patients appear to be the presence of arterial and arteriolar sclerosis which is usually non-specific. Though we would not normally do the Anti-PLA2R antibody test in a patient with low suspicion of MN, our study findings warrants further investigation and may indicate the limited usefulness of Anti-PLA2R antibody levels as a screening tool for glomerulonephritis.
P0393NEPHROTIC SYNDROME IN POST HEMATOPOIETIC STEM CELL TRANSPLANTATION PATIENTS-20 YEARS' EXPERIENCE IN A SINGLE CENTER
Authors: Ha Myung Ah , Yang Chul-Woo , Kim Yong-Soo , Park Cheol Whee
Published: June 2020

Background and Aims

Nephrotic syndrome (NS) is an extremely rare complication of hematopoietic stem cell transplantation(HCT) that usually occurs in association with chronic graft-versus-host disease. The etiology and pathogenesis of NS in HCT recipients remain unclear. There are only a few case reports and case series of NS following HCT that have been published.

Method

We reviewed the records of kidney biopsy in Seoul St. Mary’s Hospital between January, 2008 and January, 2019, and identified 32 kidney biopsy specimens from patients obtained after HCT. All patients underwent kidney biopsy for proteinuria or increased creatinine. Patient demographic data and laboratory data were collected for analysis. Responses to treatment were categorized as complete remission (CR), partial remission (PR), or non-response. The CR and PR were defined as a reduction of urine protein/creatinine ratio to <0.3g/day and urine protein/creatinine ratio between 0.31g/day and 3.4g/day, respectively.

Results

Of the 32 cases, 21 were male and 11 were female patients. The mean patient age was 43.7(range: 15-68). Average follow-up period was 46.6 months (range: 2-107 months). The mean duration between HCT and renal biopsy was 33.2 months (range: 6–206 months). The underlying diseases resulting in the need for HCT were acute myeloid leukemia, 10 patients; acute lymphoid leukemia, 9 patients; aplastic anemia, 4 patients; myelodysplastic syndrome, 3 patients; multiple myeloma, 3 patients; chronic myeloid leukemia, 1 patient; amyloidosis, 1 patient; and blastic plasmacytoid dendritic cell neoplasm, 1 patient. The most common histopathological finding was membranous glomerulonephritis (N=20). Other glomerular diseases identified were thrombotic microangiopathy, amyloidosis, C1q nephropathy, focal segmental glomerulosclerosis and diabetic nephropathy. During the follow-up period, 25 patients were treated with steroids or cytotoxic agents.18 patients were treated with angiotensin II receptor antagonist. There was no statistically significant difference between the groups in terms of ANOVA of the decrease in proteinuria according to steroids or cytotoxic agents treatment (p = 0.075) and ARB treatment. (p = 0.156)

Conclusion

Based on our result, more case will require discussion of treatment options for NS following HCT.
P0399RELAPSE TREATMENT WITH LOW DOSE OF STEROIDS IN STEROID-SENSITIVE MINIMAL CHANGE DISEASE
Authors: Álvarez Nadal Marta , Martin Irene , Villa Hurtado Daniel Eduardo , Viera Ramírez Elizabeth , Lopes Vanessa , Fernandez Lucas Milagros , Villacorta Javier
Published: June 2020

Background and Aims

Treatment of Minimal change disease (MCD) consists of high dose of steroids (HDS) for several weeks implying significant drug toxicity. On the other hand, renal relapses of steroid-sensitive MCD sometimes respond to lower doses of steroids.

Method

The objective of the study was to analyze weather low dose for steroids (LDS) is effective for treatment MCD relapses among frequently-relapsing steroid-sensitive patients. Since 2019, new relapses of steroid-sensitive patients with MCD within the Nephrology Department of Hospital Ramón y Cajal were treated with LDS. Cumulative dose of steroids, time to remission and time free of relapse were compared between relapse episodes treated with LDS and previous relapses among same patients treated with HDS.

Results

Twenty-six relapses among six steroid-sensitive MCD patients were analyzed. 15 relapses were treated with LDS and compared with 11 previous relapses among same patients treated with HDS. Mean dose of prednisone for initial treatment of the relapse was 0.89 ± 0.1 mg/kg in patients treated with HDS and 0.45 ± 0.1 mg/kg in patients treated with LDS. Mean cumulative dose of prednisone among patients treated with LDS and HSD were 1998.1 ± 1418 mg and 5611.7 ± 2326 mg, respectively. (p=0.001). Mean cumulative dose of prednisone adjusted by body weight among patients treated with LDS and HSD were 23.43 ± 14.27 mg/kg and 68.93 ± 27.05 mg/kg, respectively. (p=0.019). There was no difference in duration of treatment among HDS and LSD groups (163.45 ± 86.43 vs 138.80 ± 108.80, respectively; p = 0.525). All patients achieved complete remission after steroid therapy in both LSD and HSD groups. Mean time to remission was 18.7 days among HSD relapses and 18.4 days among the LSD relapses (p = 0.9). Time free of relapse after therapy among HDS and LDS treated relapses was 9.1 ± 5.3 months and 5.5 ± 3.5 months, respectively (p = 0.1).

Conclusion

Among steroid-sensitive MCD patients, relapse therapy with low dose of steroids (0.5 mg/kg) seems to be effective and allows minimization of steroid cumulative dose and drug toxicity.
P0402TACROLIMUS PLUS LOW DOSE PREDNISOLONE THERAPY IS MORE EFFECTIVE IN PLA2R -VE MEMBRANOUS NEPHROPATHY PATIENTS
Authors: Jaiswal Akhilesh Kumar , Prasad Narayan , Agarwal Vikas , Singh Mantabya
Published: June 2020

Background and Aims

Idiopathic Membranous Nephropathy (IMN); an autoimmune concomitant nephrotic syndrome of the adult is mainly associated with PLA2R antibody expressed on podocytes. The lack of exact mechanisms involved in the pathogenesis of IMN is transmitted to its therapeutic management. There is no standard therapy for patients with frequent relapsing or steroid-dependent IMN.

We propose the efficacy of low dose Tacrolimus (Tac) plus prednisolone and associated changes in anti-PLA2R in adult IMN.

Method

Total 101 membranous nephropathy patients were treated with combination of prednisolone 1mg/kg alt-day) and Tac 0.1mg/kg/day (trough 6-10 ng/ml first 6M and 4-6 ng/ml for next 3M) then both taper by 1/3 every month up to 12M. Out of 101 patients; 15 diabetic; 7 lupus; 1HBV and 1 ankylosing spondylitis patients were excluded. Finally; 77 Patients were followed and evaluated for the anti-PLA2R level at baseline; 3M; 6M; 12M and end of follow-up (17-61 ; median 38 months). CR; PR; relapse; and side-effects were recorded.Of the 77 patients; at 3M 60(77.92%; CR-37; PR-23); at 6M 61(79.22%; CR-53; PR-8); at 12M 53(68.86%; CR-47; PR-6) achieved remission. Eight (10.38%) relapsed and 16(20.77%) showed no response at 12M. At end of follow-up; out of 54 responsive patients 37(68.51%; CR-36; PR-1) remained in remission and 17(31.48%) patients relapsed.

Results

Out of 77 patients; 51 (66.3%) were anti-PLA2R positive. Remission rate was significantly low in PLA2R+ve than PLA2R-ve (36/51 vs 24/26; p=0.03) at 3M; (36/51 vs 25/26; p=0.009) at 6M and (31/51 vs 22/26; p=0.03) at 12M. PLA2R level was decreased by 60.38% and 77.56% at 3M and 6M respectively. There were significant correlations between PLA2R level and 24h proteinuria at baseline; 3M and at 6M. During therapy 4 patients develop cutaneous tenia; 1 osteonecrosis of the femur head; 1 corpus tunnel syndrome; 4 onset diabetes; 3 tremor; and 14 patients experienced GI symptoms. The eGFR was decreased significantly (p=0.003) by 26.5% at the end of therapy and was normalized after stopping Tac; and 5 non-responsive patients had doubling of serum creatinine and progressively deteriorated eGFR. To note; 4 females had pregnancy and successful delivery in our cohort of patients.

Conclusion

PLA2R+ve patients showed poor response compare to PLA2R-ve patients. Remission with Tacrolimus and prednisolone therapy is comparable to historical Ponticelli (Pred plus CYP) regimen. Successful pregnency was ovserved on Tac based regimen.
P0404B CELLS FROM PATIENTS WITH GRANULOMATOSIS WITH POLYANGIITIS FAIL TO REGULATE T CELL INTERFERON GAMMA RELEASE BUT DO REGULATE OTHER ASPECTS OF T CELL ACTIVATION
Authors: Puli Srinivas , Appelgren Daniel , Hellmark Thomas , Segelmark Mårten
Published: June 2020

Background and Aims

Regulatory features of B-cells have gained increased attention in patients with systemic vasculitis, including granulomatosis with polyangiitis (GPA). The aim with this study was to investigate the frequencies and phenotypes of two putative regulatory B (Breg) cell populations and assess the capacity of B-cells from GPA patients to regulate T-cell activation.

Method

37 GPA patients (22 remission and 15 active) and 31 healthy controls (HC) were included for measurement of CD19+CD24highCD27+ (memory) and CD19+CD24highCD38high (transitional) Breg cells, and 11 GPA patients in remission and 12 HC for the functional studies of B-cells. HC were matched for age and gender.

Results

Memory Breg cells were reduced in GPA both during active disease and remission compared with HC, whereas transitional Breg cells did not differ between the groups. Memory Breg cells consisted of less CD25+ cells during both active disease and remission but expressed more PD-L1 and CD86 during remission compared with active disease and HC. B-cells from GPA patients regulated T-cell proliferation and IL-17a production but failed to regulate IFN-γ production (Fig 1). The levels of IFN-γ and the IFN-γ regulated cytokine CXCL10 were elevated in patient plasma.

Conclusion

Despite reduced levels and altered phenotypes of memory Breg cells, the capacity of GPA patient B-cells to regulate T-cell proliferation and IL-17a production was unaffected. However, we found a profound inability of patient B-cells to regulate T-cell IFN-γ production. This alteration could be important for the persistent inflammation that continues during remission and results in the chronic relapsing nature of the disease
P0407THE INVESTIGATION OF SYNAPTOPODIN EXPRESSION OF PODOCYTES IN GLOMERONEPHRITIS
Authors: Zhang Zhigang
Published: June 2020

Background and Aims

Synaptopodin, a proline-rich actin-associated protein, plays an important role in the regulation of podocytes processes structures and dynamics. The mutation or lack of synaptopodin may lead to the changes of podocytes structures and functions and cause the occurrence of proteinuria. But the underlying molecular mechanisms remain primarily elusive.

Method

we used cellular and pathological experiments to observe the expression changes synaptopodin in vivo and vitrio.

Results

The results showed that the reduction expression of synaptopodin and RhoA were found in the podocytes in different nephriris of human renal biopsy as well as in rat adriamycin nephropathy. The cultured cells treated with inflammatory cytokins such as TNF, IL-1 also showed decreased synaptopodin level in podocyte, which led to low RhoA level and disarrange the actin cytoskeleton assembly, result in the abnormal changes of podocyte morphology.

Conclusion

These data preliminarily proved that synaptopodin loss in podocyte injury plays an important role in the regulation of podocyte morphology and function through RhoA signaling pathway, and further researches are required to clarify the more mechanism, which may provide new strategies and methods for the prevention and treatment of glomerular diseases.
P0409CHARACTERISTICS AND OUTCOME OF ONE HUNDRED EGYPTIAN PATIENTS OF LUPUS NEPHRITIS: A SINGLE TERTIARY CARE CENTER STUDY
Authors: Saleh Mohammed , Nassar Mohammed Kamal , Awad Ehab
Published: June 2020

Background and Aims

Renal biopsy is the “gold standard” for diagnosis of lupus nephritis (LN). It is necessary for classification and is the basis for treatment strategy decisions. This study was carried out in order to analyse the results of renal biopsy in LN patients, its effect on treatment and predictors for remission in an Egyptian cohort.

Method

The results of renal biopsies of LN patients undergoing regular follow up in the outpatient clinic of Mansoura Nephrology and Dialysis Unit (MNDU), Mansoura University Hospital, Egypt in the period between October 2017 and September 2019 were reviewed. The histopathological data were analyzed and correlated to the clinical data of the study group.

Results

A total of 100 LN patients with documented renal biopsy were enrolled in this study. The median age of the patients was 29 years. Most of the patients were females (n=89). Serum creatinine at presentation ranged from 0.57 to 13.5 mg/dl (median 1.3 mg/dl). Class IV (diffuse proliferative) LN was the most frequently encountered class, followed by Classes III, V, II and VI respectively, while class I was detected in only one patient. In proliferative classes (III and IV), the total score of activity indices, ranged from 0 to 16 (minimum–maximum). Mesangial hypercellularity was the most frequent encountered active lesions. Total score of chronicity indices ranged from 0 to 10 (minimum-maximum). Interstitial fibrosis was the most frequent chronicity index. Remission was achieved in 73 patients. Patients who achieved remission had lower serum creatinine and lower pathological chronicity score. In a multivariate logistic regression analysis, serum creatinine at presentation was the strongest predictor for renal remission in this cohort and chronicity index was the strongest predictor in proliferative classes (III and IV). Receiver operating characteristic curve (ROC curve) was done to identify the cutoff point of serum creatinine which can indicate the probability of renal recovery in proliferative and non-proliferative classes (n=100) and in proliferative classes only (n=73). A serum creatinine value of 1.65 mg/dl or less identifies the probability of renal recovery with 76% sensitivity and 71% specificity in proliferative and non-proliferative classes . A chronicity index value of 6 or less identifies the probability of renal recovery with 93% sensitivity and 58% specificity.

Conclusion

Renal biopsy is a must in LN to guide treatment and prognosis. In this Egyptian cohort, serum creatinine at presentation and pathological chronicity index score are the strongest predictors of renal response in LN patients.
P0413THE ICOS+ TREG/ICOS+ TRESP BALANCE HAS A DECISIVE ROLE REGARDING THE PRESERVATION OF THE REMISSION PHASE IN SLE PATIENTS
Authors: Schaier Matthias , Gottschalk Claudius , Kälble Florian , Zeier Martin , Steinborn Andrea
Published: June 2020

Background and Aims

An imbalance between CD4+-regulatory T-cells (Tregs) and CD4+-responder T-cells (Tresps) correlates with active disease flares in Systemic Lupus Erythematosus (SLE) patients. Both cell subsets consist of highly proliferative inducible T-cell co-stimulatory molecule expressing (ICOS+-) and less proliferating ICOS--Treg/Tresp cells.

Method

In this study we aimed to examine the role of age-dependent differentiation for maintaining the ICOS+-Treg/ICOS+-Tresp or ICOS--Treg/ICOS--Tresp balance in SLE remission patients compared to active disease patients and to evaluate the influence of proliferation inhibitor or glucocorticoid therapy concerning the maintenance of these equilibria.

Results

In 83 healthy volunteers, the ratio of ICOS+-Tregs/ICOS+-Tresps increased significantly with age, while that of ICOS--Tregs/ICOS--Tresps did not change. In 86 SLE remission patients, medication controlled disease activity was associated with an age-independently increased ratio of both ICOS+-Tregs/ICOS+-Tresps and ICOS--Tregs/ICOS--Tresps. In 13 active disease patients this increased ICOS+-Treg/ICOS+-Tresp ratio could not be maintained, due to an age-dependent earlier terminal differentiation of ICOS+-Tregs than of ICOS+-Tresps. The increased ratio of ICOS--Treg/ICOS--Tresp was maintained in active disease patients, but it decreased with age. This was attributable to an age-independent aberrant differentiation of ICOS--Tresps and a resulting loss of age-dependent differentiation of ICOS--Tregs. Especially the administration of proliferation inhibitors (azathioprine or mycophenolic acid) ensured prolonged differentiation and maintenance of functional ICOS+-Tregs with age. There was a similar but weaker effect of this medication on ICOS+-Tresps, causing a significant decrease of these cells with age. The proliferation capacity was neither affected in ICOS+-Tregs/Tresps nor in ICOS--Tregs/Tresps. As a result, the ratio of ICOS+-Tregs/ICOS+-Tresps increased significantly with age and kept the patients in remission. In contrast, glucocorticoids increased the differentiation of ICOS--Tregs especially in younger individuals, but had an adverse effect on their proliferation capacity.

Conclusion

Our data reveal a crucial role of the ICOS+-Treg/ICOS+-Tresp balance for the maintenance of self-tolerance and avoidance of disease flares in SLE. The used immunosuppressive therapy, especially the administration of proliferation inhibitors, has a decisive effect on the preservation of regular differentiation of all Treg/Tresp subsets with age, and most importantly avoids the terminal differentiation and immune senescence of ICOS+-Tregs.
P0414URINARY HEPCIDIN AS A BIOMARKER OF NEPHRITIS IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS
Authors: Saleh Marwa , Eldeep Ahmed , L Abdelsalam Adel , El-baiomy Azza , Awad Ehab
Published: June 2020

Background and Aims

Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) that is associated with poor prognosis. The current available urinary biomarkers are neither sensitive nor specific for diagnosing LN. This study was undertaken to investigate whether urinary hepcidin represents a marker of nephritis in SLE patients.

Method

A cross-sectional study was conducted with 3 study groups compromising 30 patients with biopsy proven LN, 30 patients with non-nephritis SLE and 20 healthy control. Spot urinary samples were collected from all participants and the levels of hepcidin in urine were measured by ELISA, 24 h urinary proteins, urinary and serum creatinine were measured.

Results

Urinary hepcidin was significantly higher in LN patients than in non-nephritis SLE and control (470, 258, 43.0 ng/mg creatinine respectively) (P < 0.001) as shown in figure 1. Urinary hepcidin was significantly correlated with serum creatinine (P 0.017) and 24 hours urinary proteins (P 0.003). ROC curve cut-off values of urinary hepcidin were 4.3000, Area under curve (AUC) of hepcidin was 0.553, with sensitivity (SN) of 63.3%, specificity (SP) of 60%, Positive predictive value (PPV) 70.4, negative predictive value (NPV) 52.2 in SLE patients as shown in table 1 and figure 2.

Conclusion

Although urinary hepcidin level was significantly higher in LN patients than in non-nephritis SLE and control, it failed to discriminate patients with LN from those without. Further studies are still needed before considering urinary hepcidin as a non-invasive diagnostic marker of LN.
P0417THE ABSENCE OF C3 DEPOSIT IN MEMBRANOUS NEPHROPATHY IS ASSOCIATED WITH SPONTANEOUS REMISSION
Authors: Rabasco Cristina , Martínez Ana , Ortega Rosa , Espinosa Mario
Published: June 2020

Background and Aims

Membranous nephropathy (MN) is the most common cause of biopsied nephrotic syndrome in adults. Recently, it has been reported that the pathogenesis of MN may be associated with an activation of the complement system. The pathway of activation is not clearly established. The intensity of C3 deposition could be a good marker of this activation in MN as has been shown in other diseases (IgA nephropathy, crescentic GN). The aim of this study is to evaluate clinical-pathological data in a cohort of patients with MN and the significance of glomerular C3 staining as a possible predictor of renal outcomes.

Method

We analysed patients with idiopathic MN biopsied in our department between January 2000 and December 2019, excluding those who had no material for IF (n = 115). The patients were divided into positive (87 cases) and negative (28 cases) based on glomerular C3 deposition. We assessed the clinical and histological characteristics and the percentage of spontaneous remission (SR) and end-stage renal disease (ESRD).

Results

A total of 115 patients with MN were followed with a median follow-up of 65 (25-161) months. We found no differences in baseline characteristics between both groups, with the exception that patients with C3 deposit had less albumin at the time of biopsy that negative patients [2.4 (2-2.9) vs 2.8 (2.3-3.1) g/dl, P=0.011)].

Patients with C3-negative had a higher percentage of SR than patients with C3-positive (75 vs 24%, P = 0.000) and less need for immunosuppressive treatment (18 vs 56%, P =0.001). At the most recent follow-up, C3-positive group had higher creatinine [1.42 (0.8-1.7) vs 0.97 (0.71-1) mg/dl, P=0.045] and proteinuria [1.64 (0.08-3.2) vs. 0.62 (0.05-0.79) g / 24h, P = 0.039]. Regarding histology, we found no differences in glomerular sclerosis, tubular atrophy and interstitial fibrosis. The renal survival analysis showed no statistically significant differences between both groups (P = 0.091). We analysed a subgroup of patients (n = 23) with antibodies against the phospholipase receptor on blood at the time of the biopsy (13/23 were positive). 84% of this positive group presented C3-positive in the renal biopsy vs 25% of the C3-negative group (P =0.008).

Conclusion

Patients without C3 staining show a higher rate of SR and less need for immunosuppressive treatment than patients with C3-positive.

These results would support the theory that complement activation in this entity can play an important role.

It is possible that these patients with negative C3 deposit represent a MN with evolution to SR and in these patients and that these patients do not need immunosuppressive treatment.
P0425MEMBRANOUS NEPHROPATHY IN TURKEY: TURKISH SOCIETY OF NEPHROLOGY GLOMERULER DISEASES (TSN-GOLD) DATABASE RESULTS
Authors: Yildiz Abdulmecit , Ulu Memnune Sena , Oruc Aysegul , Ucar Ali Riza , Ozturk Savas , Alagoz Selma , Eren Necmi , Kocyigit Ismail , Koksal Cevher Simal , Haras Ali Burak , Sumnu Abdullah , Arinsoy Turgay , SAHIN Garip , Suleymanlar Gultekin , Cavdar Caner , Kumru Şahin Gizem , Kurultak Ilhan , Unsal Abdulkadir , Manga Sahin Gulizar , Kazan Sinan , Vatansever Bulent , Dikec Mehmet , Dursun Belda , Sayarlioglu Hayriye , Turkmen Kultigin , Artan Ayse Serra , Aktas Nimet , Yilmaz Zulfikar , Behlül Ahmet , Dheir Hamad , Kutlay Sim , Seyahi Nurhan
Published: June 2020

Background and Aims

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in the adult population. The aim of our study is to determine the demographic and clinical characteristics and biopsy findings of the patients diagnosed with MN in our country.

Method

The study included 991 patients with renal biopsy who were followed in 47 nephrology clinics and enrolled in the database of Turkish Nephrology Primary Glomerular Diseases (TSN-GOLD) Working Group between May 1, 2009, and June 1, 2019. The demographic and clinical characteristics and biopsy findings of all patients included in the study were analyzed.

Results

The mean age of patients included in our study was 46±14.8 years and the gender distribution was (M / F, 582/409). 80.3% (n = 796) of the patients had nephrotic proteinuria at the time of diagnosis. Before the biopsy, the PLAR2 antibody was examined in 137 patients and positive in 71.5% (n = 98) patients. Hypertension was present in 34.6% (n = 343) of the patients. Mean estimated glomerular filtration rate was 93.9±32.8 ml/min/1.73 m2, albumin level was 2.7 ± 0.2 mg/dL, proteinuria level in urine was 7,1±6,4 gr/day and total cholesterol level was 295±3.7 mg/dL. On light microscopy, baseline membrane thickening was found in 92% (n=907) and interstitial inflammation in 53% (n=524) specimens. In immunofluorescence staining, 3 (+) IgG accumulation was highest in 578 (58.3%) of the specimen.

Conclusion

This multicentre study is the largest study to analyze clinical, laboratory, and biopsy specimens of MN patients at the time of biopsy in our country. The findings are consistent with the literature. Prospective follow-up results of these patients will help us to understand the renal prognosis and treatment response better.
P0426HISTOLOGICAL PREDICTORS OF RENAL PROGNOSIS IN LUPUS NEPHRITIS: WHICH COMPARTMENT MAKES THE DIFFERENCE?
Authors: Stefan Gabriel , Stancu Simona , Georgescu Carmen , Zugravu Adrian Dorin , Petre Nicoleta , Mircescu Gabriel
Published: June 2020

Background and Aims

Lupus nephritis (LN) encompasses a spectrum of glomerular, tubulointerstitial, and vascular lesions; we aimed to evaluate which compartment injury has renal prognostic value.

Method

We retrospectively examined the renal outcome at 31 December 2015 of 66 patients (age 36 [28-52] years; 76% female; eGFR at baseline 60.8 [24.4-78.1] mL/min) who were diagnosed with lupus nephritis by kidney biopsy during 2010-2015. Data regarding the clinical presentation, renal function, histology (presence/absence of lesions - Table 1; ISN/RPS classification) and treatment were retrieved from the electronic patients’ files. We used a composite endpoint in the survival analysis (Cox proportional hazard models, CPH): renal replacement therapy initiation, doubling of serum creatinine and death, whichever came first.

Results

Nephrotic syndrome was the most frequent form of presentation (42%), followed by nephritic (24%) and nephrotic-nephritic (15%). Most of the patients received immunosuppression treatment (97%, 70% cyclophosphamide regimen). Twenty-five patients (38%) reached the composite endpoint. They were older, male more often, had higher mean arterial pressure (MAP), lower serum albumin, decreased eGFR and higher proteinuria. Moreover, they were in class IV LN and had glomerulosclerosis more frequently. Median renal survival for the entire cohort was 4.4 (95%CI, 2.3-6.5) years. In the multivariatle CPH for the histological predictors, only ISN/RPS classification and tubular atrophy were associated with renal survival (Table 1). In a CPH that included clinical, histological and treatment variables, only lower eGFR (0.97 (95%CI, 0.95-0.99)), MAP (1.03 (95%CI, 1.00-1.06)) and tubular atrophy (4.52 (95%CI, 1.50-13.55)) remained as independent predictors of renal survival.

Conclusion

Tubular atrophy seems to be an important prognostic sign in LN; therefore, greater importance should be given to the tubulointerstitial compartment evaluation.
P0438PREDICTORS OF TREATMENT RESPONSE AND LONG-TERM OUTCOME IN PATIENTS WITH PAUCI-IMMUNE GLOMERULONEPHRITIS AND SEVERE RENAL DYSFUNCTION AT DIAGNOSIS
Authors: Lionaki Sophia , Marinaki Smaragdi , Kalogeropoulos Petros , Liapis George , Gakiopoulou Harikleia , Kapsia Helen , Tzioufas Athanasios , Boletis Ioannis
Published: June 2020

Background and Aims

Severe kidney involvement represents a frequent clinical scenario for patients with pauci-immune (PI) vasculitis. We aimed to explore the factors, which are associated with prognosis, in short and long term, following administration of appropriate immunosuppressive therapy.

Method

Patients were included if they had biopsy proven PI glomerulonephritis (GN) with estimated GFR<20 ml/min/1.73 m2 or dialysis requirement at presentation, received standard immunosuppression and were followed for a minimum period of one year. We recorded clinical, laboratory and histopathological parameters at diagnosis, at 3 months, at 1 year and at the end of follow up. Outcomes of interest included response to treatment, end stage kidney disease (ESKD), and death. Treatment response was defined by the ability to come off dialysis with an eGFR>20 ml/min/1.73 m2 with no signs of vasculitis. Histopathological evaluation included arteriosclerosis, % of normal glomeruli, activity index, chronicity index.

Results

A total of 83 patients, with a mean age of 59.6 (15.05) years were included. There were, 45 males (54.2%). After 3 months, 59 patients (71.1%) had responded to immunosuppressive therapy, 16 (19.3%) were dialysis depended, 5(6.02%) died and 2 were lost in follow up. By the end of the 1st year, 59 patients (71.1%) achieved remission, 16(19.3%) ended up in ESKD and 6(7.4%) died. Factors which were associated with treatment response included MPO-ANCA positivity [odds ratio OR:3.9, 95%CI (1.13-13.37) p=0.03], eGFR>10ml/min/1.73m2 at presentation [OR:2.5, 95% CI(0.86-7.30), p=0.009], normal glomeruli >10% [OR:3.8, 95%CI (1.24-12.1), p=0.02], and chronicity index more than 6 [OR:6.2, 95% CI(1.77-22.4), p=0.004]. Risk factors associated with ESKD included non-response to immunosuppressive therapy [Relative Risk RR:0.05, 95%CI (0.01-0.2) p<0.0001)], normal glomeruli<10% in the diagnostic biopsy [RR: 2.9, 95% CI (1.38-6.32), p=0.005] and age>75 years [RR:3.2, 95% CI (0.9-10.6) p=0.055]. Two of the 6 deaths were disease related.

Conclusion

A significant proportion of patients with PI-GN, who presented with severe renal dysfunction, responded to immunosuppressive therapy and recovered renal function approximately 3 months after initiation of therapy. The most important risk factors for ESKD were age>75 years, <10% normal glomeruli in the diagnostic kidney biopsy and non-response to immunosuppressive therapy.
P0439THE RELATIONSHIP BETWEEN SOCIO-ECONOMIC STATUS AND RENAL VASCULITIS IN SCOTLAND
Authors: Aiyegbusi Oshorenua , Frleta-Gilchrist Marina , MacKinnon Malcolm , Traynor Jamie , Stevens Kate , Geddes Colin C , McQuarrie Emily
Published: June 2020

Background and Aims

Individuals living in areas of multiple socioeconomic deprivation have reduced life expectancy and experience health inequalities. Chronic kidney disease is more common in areas of social deprivation and these patients are more likely to develop end stage kidney disease. Vasculitis is a rare but significant cause of kidney disease. The impact of socioeconomic status on disease activity or outcomes in patients with ANCA Associated Vasculitis (AAV) is yet to be fully explored. The aim of this study was to establish whether there is an association between the incidence of biopsy-proven renal vasculitis and socioeconomic status, as measured by the Scottish Index of Multiple Deprivation (SIMD).

Method

Using the Scottish renal biopsy registry, we identified all adult native renal biopsies performed across Scotland between 2014 and 2018 with a diagnosis of AAV. Patient’s postcode and SIMD (2016) rank were recorded. Patients were separated into quintiles of SIMD rank. Baseline demographics were recorded. We derived the denominator population from the 2016 SIMD census. Data were calculated per million population (PMP) served.

Results

339 biopsy proven cases of AAV were identified. 6 cases were excluded as postcode was unavailable. Overall, mean age was 65.9 (±13.0) years and 45% of patients were male. At time of diagnosis, mean estimated glomerular filtration rate (eGFR) was 61.7 (±25.7) ml/min/1.73m2 and median urinary protein creatinine ratio (uPCR) was 134mg/mmol (IQR 64-21). Microscopic Polyangiits n=205(65%) was more common than Granulomatosis with Polyangiits n=128(35%). The incidences of kidney biopsy proven AAV were similar across all quintiles of deprivation. In the most deprived 20% of population, incidence rate of kidney biopsy proven AAV was 11.2 per million person-years vs 13.0 per million person-years in least deprived 20% of population. Patients in areas of greatest relative deprivation were younger (64.0 (±12.3) vs. 68.1 (±12.7) years) and had slightly less proteinuria at diagnosis (99mg/mmol (IQR 35-211) vs. 138mg/mmol (IQR 78-281)) when compared to patients living in least deprived areas. However, there was no difference in level of renal function at diagnosis (33.8 (±29.6) ml/min/1.73m2 vs 31.5 (±23.2) ml/min/1.73m2).

Conclusion

Our complete national dataset shows that there is no significant difference in incidence of renal AAV across the spectrum of socioeconomic deprivation. The analysis of renal function at presentation suggests no evidence of an association between deprivation and delay in diagnosis in a healthcare system free at the point of access.
P0442RELATED FACTORS IN THE DEVELOPMENT OF LUPUS NEPHRITIS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: Ribas Andres , Galcerán Isabel , Outón Sara , Salman Tarek , Barrios Clara , S. Ochoa Adriana , Buxeda Anna , Sans Laia , Pascual Julio , Rodriguez Eva
Published: June 2020

Background and Aims

Lupus Nephritis (LN) is a severe complication of Systemic Lupus Erytemathosus (SLE). This is the main reason why identifying predisposing factors to differentiate patients at risk of developing LN is so important.

Method

Retrospective study of patients with SLE diagnosed between years 2008-2018 in our center. Demographic, clinical and analytical data have been collected.

Results

We included 171 patients, 48 (28%) with diagnose of LN. Age at diagnose of SLE was 39,51 ± 15,40 years, being more frequent in women 151 (87,5%). Time of follow-up since SLE diagnose until development of LN was of 3 ± 5, 3 years. Respectful to the LN classification we found: 4 (8%) class I LN, 6 (12.5%) class II LN, 15 (31.2%) class III LN, 19 (39.5%) class IV LN and 4 (8%) class V LN. At diagnose of SLE, the following variables, where related to developing LN: CH50 [HR: 1,039; CI (95%): 1,004-1,064; p=0,024], C3 [HR: 1,029; CI (95%): 1,016-1,042; p<0,001, titer of Anti- DNACrithidia [HR: 4,364; CI(95%): 1,26-15,064; p=0,02], AntiSM [HR: 4,634, CI (95%) 1,76-12,17, p=0,002], ACA IgG [HR: 7,5; CI (95%): 2,3 -24,449; p=0,001] and Lupus anticoagulant [HR: 4,97; CI (95%): 1,591-15,533; p=0,006]. Treatment with hidroxicloroquine is a protective factor against developing LN [HR: 0,17; CI (95%): 0,063-0,511; p=0.001]. At diagnose of LN, complement factors and titer of anti-DNA crithidia show a positive correlation when compared to the initial determinations: C3 [r= 0,605 (p<0,001]); C1q [r= 0,861 (p=0,006)]; CH50 [r= 0,981 (p<0,001), anti- DNACrithidia [r= 0,529 (p<0,001)], anti-Sm [r=0.8, )p=0.001)].

Conclusion

Consumption of complement factors, high titers of anti-DNAcrithidia, Anti-SM, ACA IgG and Lupus anticoagulant are related to a future LN development at SLE diagnose. Moreover, we see an increase of their titer once we diagnose LN. Otherwise, treatment with hidroxicloroquine seems to be a protective factor.