Diffuse Proliferative Lupus Nephritis Research Articles

STAT3 inhibition ameliorates renal interstitial inflammation in MRL/lpr mice with diffuse proliferative lupus nephritis

Background and objectives Acute kidney injury (AKI) is one of the most common and severe clinical syndromes of diffuse proliferative lupus nephritis (DPLN), of which poor prognosis is indicated by aggravated renal function deterioration. However, the specific therapy and mechanisms of AKI in DPLN remain to be explored. Methods The correlation between AKI and clinical pathological changes in DPLN patients was analyzed. Expression of STAT3 signaling was detected in MRL/lpr mice with DPLN using immunohistochemical staining and immunoblotting. Inhibition of STAT3 activation by combination therapy was assessed in MRL/lpr mice. Results Correlation analysis revealed only the interstitial leukocytes were significantly related to AKI in endocapillary DPLN patients. MRL/lpr mice treated with vehicle, which can recapitulate renal damages of DPLN patients, showed upregulation of STAT3, pSTAT3 and caspase-1 in renal cortex. FLLL32 combined with methylprednisolone therapy significantly inhibited the STAT3 activation, improved acute kidney damage, reduced the interstitial infiltration of inflammatory cells and decreased the AKI incidence in MRL/lpr mice. Conclusion STAT3 activation may play an important role in the pathogenesis of DPLN and the development of AKI. Hence, STAT3 inhibition based on the combination of FLLL32 with methylprednisolone may represent a new strategy for treatment of DPLN with AKI.

#1707 Antiphospholipid antibodies in lupus nephritis

Abstract Background and Aims Antiphospholipid antibodies (aPL) constitute a heterogeneous family of antibodies against anionic phospholipids or phospholipid-binding proteins. They may occur in association with autoimmune diseases, infections, and sometimes in the general population. Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE). The aim of this study was to investigate the association of aPL with clinical activity, renal damage, renal activity and outcomes in patients with LN. Method A total of 157 patients (11 male, 146 female, age between 17 and 58 years) with LN were included in this study. The International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of LN was used to classify the patients into LN subsets. Histopathological renal activity and damage were estimated using the Activity Index (AI) and Chronicity Index (CI), respectively. Levels of anticardiolipin (aCL) antibodies, anti-β2-glycoprotein I (anti-β2-GPI) antibodies and lupus anticoagulant (LAC) were measured, and other clinical and pathological data were also obtained. Long-term renal outcome was determined by the estimated glomerular filtration rate (eGFR) and the Chronic Kidney Disease stage, after a median follow-up of 20,5 ± 8, 7 years, counting from the occasion of the first renal biopsy. Renal and extra-renal symptoms were analyzed. Patients which have more than one class LN features, were excluded from the study. The treatment includes standard treatment for LN, inhibitors of the angiotensin system in patients with hypertension and proteinuria, steroids, anticoagulants, cyclophosphamide, mycophenolate mofetil, azathioprine. Results LN patients were classified according to the baseline renal biopsies as patients with: minimal mesangial LN (4), mesangial-proliferative LN (30), focal proliferative LN (31), diffuse proliferative LN (48), membranous LN (44). aPL antibodies were detected in 89 (56,69%) patients, aCL antibodies – in 72 (45,86%), anti-β2-GPI antibodies – in 58 (36,94%) and LAC were detected in 46 (29,30%) patients. None of these patients had a concomitant diagnosis of antiphospholipid syndrome nephropathy. Follow-up was similar between aPL-positive and aPL-negative patients. LN patients with positive aPL antibodies had significantly higher SLEDAI (p < 0,05), anti-dsDNA levels (p < 0,05), anti-ribosomal-P antibodies levels (p < 0,05), anti-C1q antibodies (p < 0,05), lower serum C3 (p < 0,005) and C4 (p < 0,05) levels, and higher intensity of complement C3 (p < 0,05) deposits in kidney tissue than the aCL antibody–negative LN patients. aPL-seropositivity was associated with more rapid decline in eGFR (–1,06 mL/min/year compared to –0,45 mL/min/year in aPL-seronegative patients) and showed inferior patient survival (89,8% and 67,9% at 10 and 15 years, respectively, compared to 97,3% and 76% in aPL-seronegative patients). No significant correlation was found between serum aPL antibodies levels and activity or chronicity index scores in renal biopsies at baseline, ANA levels, or age. Conclusion We concluded that aPL-seropositivity are correlated with clinical activity in patients with LN and are associated with inferior long-term patient survival.

Renal Manifestation of Mixed Connective Tissue Disease

A young female presented with facial puffiness and swelling in both lower limbs for 3 months, distension of the abdomen, and breathlessness on exertion for 1 month with a history of hypertension and hypothyroid on regular treatment. On general physical examination, there were pallor, bilateral pitting edema, tachycardia, and blood pressure of 190/100 mmHg. Abdominal examination revealed shifting dullness. Respiratory and cardiovascular systems were normal. Fundoscopy revealed Grade 1 papilledema, and the rest of the neurological examination was unremarkable. Investigations showed normocytic normochromic anemia, serum creatinine of 1.6 mg/dl, and hypoalbuminemia; urine R/E showed significant proteinuria; and anti-U1 ribonucleoprotein particle antibodies were positive. Two-dimensional echocardiography showed mild concentric left ventricular hypertrophy and mild pericardial effusion. Ultrasonography abdomen showed bilateral renal parenchymal disease and moderate ascites. Renal biopsy revealed diffuse proliferative glomerulonephritis and lupus nephritis Class IV. Renal manifestation is very rare in mixed connective tissue disease as an initial presentation.

Lupus nephritis – modern aspects of diagnosis and therapy. Part I

Lupus nephritis (LN) is considered to be one of the most frequent severe manifestations of systemic lupus erythematosus (SLE), its various colonic manifestations occur in at least 50% of SLE patients, both at the onset and at various stages of the disease, and develop LN is considered one of the most important predictors of mortality in SLE. The structure of nephritis is dominated by diffuse proliferative LN with clinical and morphological signs of progression and the rapid development of terminal renal failure. SLE is diagnosed based on the 2019 EULAR/ACR (European Alliance of Associations for Rheumatology/American College of Rheumatology) diagnostic classification criteria. To confirm the diagnosis, evaluate the prognosis, and choose the tactics of treating the dis-ease, all patients in the absence of contraindications require a kidney biopsy. In addition to LN, the spectrum of SLE-associated renal lesions includes vascular pathology represented by thrombotic microangiopathy, lupus vasculopathy or vasculitis, tubulointerstitial injury, and lupus podocytopathy.

Glomerular endothelial expression of type I IFN-stimulated gene, DExD/H-Box helicase 60 via toll-like receptor 3 signaling: possible involvement in the pathogenesis of lupus nephritis

Background Sustained type I interferon (IFN) activation via Toll-like receptor (TLR) 3, 7 and 9 signaling has been reported to play a pivotal role in the development of lupus nephritis (LN). Although type I IFN activation has been shown to induce interferon-stimulated genes (ISGs) expression in systemic lupus erythematosus, the implication of ISGs expression in intrinsic glomerular cells remains largely unknown. Methods We treated cultured human glomerular endothelial cells (GECs) with polyinosinic-polycytidylic acid (poly IC), R848, and CpG (TLR3, TLR7, and TLR9 agonists, respectively) and analyzed the expression of DExD/H-Box Helicase 60 (DDX60), a representative ISG, using quantitative reverse transcription-polymerase chain reaction and western blotting. Additionally, RNA interference against IFN-β or DDX60 was performed. Furthermore, cleavage of caspase 9 and poly (ADP-ribose) polymerase (PARP), markers of cells undergoing apoptosis, was examined using western blotting. We conducted an immunofluorescence study to examine endothelial DDX60 expression in biopsy specimens from patients with LN. Results We observed that endothelial expression of DDX60 was induced by poly IC but not by R848 or CpG, and RNA interference against IFN-β inhibited poly IC-induced DDX60 expression. DDX60 knockdown induced cleavage of caspase 9 and PARP. Intense endothelial DDX60 expression was observed in biopsy specimens from patients with diffuse proliferative LN. Conclusion Glomerular endothelial DDX60 expression may prevent apoptosis, which is involved in the pathogenesis of LN. Modulating the upregulation of the regional innate immune system via TLR3 signaling may be a promising treatment target for LN.

Clinicopathological Study of Males with Lupus Nephritis: Pathologist's Experience at a Tertiary-Care Center.

Background:Systemic lupus erythematosus (SLE) is an autoimmune systemic disorder, more common in females of reproductive age-group as compared with males. There are very few studies regarding lupus nephritis (LN) in males. Hence, we decided to study the clinical and pathological findings of LN in males.Materials and Methods:We carried out a retrospective study over a period of 5 years (January 2014–December 2018) on indicated native renal biopsies from male patients with LN. We analyzed the clinical, laboratory, and histological findings of these patients.Results:Renal biopsies were performed on 228 patients with LN, of which 29 (12.72%) biopsies were in male patients. The mean age at presentation was 28.3 ± 12.98 years. Edema (65.5%) was the most common clinical feature followed by arthritis (27.58%), fever (27.58%), and skin rash (24.1%). The mean values for 24 hours urinary protein, serum double-stranded DNA, serum antinuclear antibody, and serum complement C3 were 4.98 ± 2.91 g, 137.7 ± 91.93 IU/mL, 2.96 ± 1.78, and 65.07 ± 36.30 mg/dL, respectively. On histology, the most common class of LN was Class IV (34.48%) followed by Class V (20.68%), combined Class IV + V (20.68%), Classes II, III, and III + V.Conclusion:LN can affect males, although the prevalence is lower than in females. The incidence of LN in our study was 12.7% with the most common histological class being diffuse proliferative LN.

A Case of Class IV Diffuse Proliferative Lupus Nephritis in a Hispanic Woman with Underlying Systemic Lupus Erythematosus

A Case of Class IV Diffuse Proliferative Lupus Nephritis in a Hispanic Woman with Underlying Systemic Lupus Erythematosus

Successful therapeutic response with sequential therapy of rituximab and belimumab in a hispanic patient with refractory lupus nephritis

Lupus nephritis (LN) is the most common severe organ manifestation of systemic lupus erythematosus (SLE). Life expectancy and renal survival is reduced in these patients. A partial remission in LN is associated with a significantly better patient and renal survival rate compared with no remission. We report the case of a 27-year-old Hispanic patient with diffuse proliferative lupus nephritis (grade IV with high activity index) managed with induction therapy with mycophenolate mophethyl (MMF, 1000 mg daily escalating to 3000 mg daily and prednisone (PDN) 1 mg/kg/day. Progression of proteinuria with preserved renal function and extra-renal activity were observed (alopecia). Re-induction with IV cyclophosphamide (CYC, 1 gr.) and pulse IV methylprednisolone (500 mg for three days) was administered, followed by a lower starting dose of PDN (0.5 mg/kg/day). Treatment failure was observed. A second renal biopsy evidenced renal damage (chronicity index 4/12 and activity index 4/24). The patient also developed non-renal clinical manifestations (malar rash, oral ulcers and arthritis). Treatment with IV rituximab (RTX) 1000 mg X2 associated with MMF 1000 mg per day and IV methylprednisolone 500 mg X3 was initiated, followed by PDN 0.5 mg/kg/day with a dose-tapering scheme similar to CYC re-induction. Treatment continued with IV Belimumab (BLM) 600 mg every month associated with MMF 1000 mg per day. Sequential therapy with RTX + BLM showed a partial renal and complete extra-renal response in a patient with severe lupus despite two 2 immunosuppressive treatment schemes.

CLINICAL AND HISTOPATHOLOGICAL CHARACTERIZATION OF LUPUS NEPHRITIS IN A TERTIARY HEALTH CENTRE, NORTH-EASTERN NIGERIA: REPORT OF FIVE CASES.

Background: Lupus nephritis (LN) is an immune complex glomerulonephritis that complicates up to 40% of SLE patients. A kidney biopsy is required for diagnosis and staging of the disease. Case report: We report a cohort of five patients with LN from a tertiary health facility in northeastern Nigeria. The five patients were all women with age ranging from 26 to 55 years, and eGFR of between 6 to 154ml/minute. Four patients had normal kidney size and were biopsied whereas 1 patient had contracted kidney. Diffuse proliferative LN (Class IV) was seen in two patients while the other two patients had glomerular sclerosis (Class VI). Patients were given induction with methylprednisolone and mycophenolate mofetil (MMF). At one year follow up 2(40%) patients were in remission, 1(20%) was on maintenance hemodialysis and 2(40%) patients had died. Conclusion: Lupus nephritis is a common complication of SLE in northeastern Nigeria. Patients have features of advanced kidney disease at presentation.

CLINICAL AND HISTOPATHOLOGICAL CHARACTERIZATION OF LUPUS NEPHRITIS IN A TERTIARY HEALTH CENTRE, NORTH-EASTERN NIGERIA: REPORT OF FIVE CASES.

Background: Lupus nephritis (LN) is an immune complex glomerulonephritis that complicates up to 40% of SLE patients. A kidney biopsy is required for diagnosis and staging of the disease. Case report: We report a cohort of five patients with LN from a tertiary health facility in northeastern Nigeria. The five patients were all women with age ranging from 26 to 55 years, and eGFR of between 6 to 154ml/minute. Four patients had normal kidney size and were biopsied whereas 1 patient had contracted kidney. Diffuse proliferative LN (Class IV) was seen in two patients while the other two patients had glomerular sclerosis (Class VI). Patients were given induction with methylprednisolone and mycophenolate mofetil (MMF). At one year follow up 2(40%) patients were in remission, 1(20%) was on maintenance hemodialysis and 2(40%) patients had died. Conclusion: Lupus nephritis is a common complication of SLE in northeastern Nigeria. Patients have features of advanced kidney disease at presentation.

Lupus nephritis with an unusual histopathological pattern

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect multiple organs. When the kidney is involved it is generally termed lupus nephritis (LN), and is a major contributor to the morbidity and mortality associated with SLE. The classic pattern of lupus nephritis in a renal biopsy is an immune complex mediated glomerulonephritis. The presence of crescents, in diffuse proliferative lupus nephritis, and serologic positivity for antineutrophil cytoplasmatic antibodies (ANCA), more often antimyeloperoxidase than anti-proteinase 3, has been linked with specific clinicopathological features, poor treatment response and a worse kidney survival. Clinical case: We present the case of a 19-year-old male, without relevant past medical history, who presented severe headaches, hypertension and peripheral edema. The blood analysis revealed hemoglobin (Hb) 7.6 g/dL, creatinine (Cr) 2.64 mg/dL, blood urea nitrogen (BUN) 101 mg/dL, and urine analysis, hematuria and nephrotic proteinuria. The autoimmunity panel results were consistent with SLE paired with positivity for ANCA-proteinase 3 antibody. A renal biopsy revealed crescentic glomerulonephritis with fibrinoid necrosis and Bowman capsule rupture. The patient was diagnosed with class IV LN. The initiation treatment consisted of cyclophosphamide (CIPH) and prednisolone (PDN). At the 6-month follow-up, CIPH was stopped and mycophenolate mofetil (MMF) initiated as maintenance therapy, combined with PDN. Although microscopic hematuria and C3 consumption were still present (a new biopsy was pondered but the patient refused any further invasive diagnostic measures), C1q levels decreased from 26.6 to 19.3 U/ml (negative if < 20 U/ml) and anti-dsDNA was also negative with progressive declination of the degree of proteinuria. The creatinine levels returned to normal. Conclusion: The authors emphasize the importance of this class IV LN, influenced by the association with anti-proteinase 3, due to the implications in the histopathological pattern and in therapy selection. In this specific case kidney function, proteinuria and lupus activity had an important decrease without significant complications with the chosen treatment.

Glomerulonephritis in AKI: From Pathogenesis to Therapeutic Intervention.

Acute kidney injury (AKI) is increasingly emerging as a global emergency. Sepsis, major surgery, and nephrotoxic drugs are the main causes of AKI in hospitalized patients. However, glomerulonephritis accounts for about 10% of AKI episodes in adults, mainly related to rapidly progressive glomerulonephritis resulting from granulomatous polyangiitis (GPA, Wegener granulomatosis), microscopic polyangiitis (MPA), and anti-glomerular basement membrane (GBM) disease. Also, diffuse proliferative lupus nephritis, immunoglobulin A nephropathy, post-streptococcal glomerulonephritis, mixed cryoglobulinemia, mesangiocapillary glomerulonephritis, membranous nephropathy, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and scleroderma can induce acute renal failure. Early diagnosis of AKI due to glomerulonephritis is crucial for prompt, effective management to improve short- and long-term outcomes. Kidney biopsy is the gold standard for the diagnosis of glomerular disease, but it is not frequently performed in critically ill patients because of their clinical conditions. In this setting, a growing number of diagnostic assays can support the working hypothesis, including antineutrophil cytoplasmic antibodies (ANCAs), anti-double-stranded DNA antibodies, anti-GBM antibodies, antistreptolysin O and anti-DNase B antibodies, cryoglobulins, antiphospholipid antibodies, and complement levels. Therapeutic strategies in AKI patients with glomerulonephritis include high-dose corticosteroids, cyclophosphamide, and plasma exchange. This article reviews the wide spectrum of glomerulopathies associated with AKI, describing the immunological mechanisms underlying glomerular diseases and presenting an overview of the therapeutic options.

Clinicopathological spectrum of two common conditions encountered in renal biopsies: acute diffuse proliferative glomerulonephritis and lupus nephritis

Background: Acute diffuse proliferative glomerulonephritis (ADPGN) and lupus nephritis (LN) are commonly encountered conditions in renal biopsies. ADPGN is usually a self-limiting childhood disease occurring commonly after streptococcal infection. LN is a common complication of systemic lupus erythematosus (SLE) with diverse clinical and histological features. Objectives: The objective of this study is to describe the clinico-pathological spectrum of ADPGN and LN in renal biopsies. Method: A retrospective-descriptive study was done by retrieving all renal biopsies (1225) received in the year 2018 at the Department of Pathology, Faculty of Medicine, University of Peradeniya. Biopsies diagnosed as ADPGN and LN were selected. Results: Out of all renal biopsies (1225), 63(5.1%) were diagnosed as ADPGN and 92(7.5%) as LN. ADPGN was seen in an age range of 3-78 years. 24(38.1%) were children and 39(61.9%) were adults. Nephritic syndrome (NS) was the commonest presentation in both children and adults (n=23,36.5%) while 13(20.6%) showed nephrotic-nephritic mixed picture (NNMP). Cellular crescents were seen in 11 patients (17.4%) and most were adults with NNMP. Tubular injury was seen in 19 (30.1%) and most were children with NNMP. 34 (53.9%) patients showed classic uncomplicated ADPGN. Immunofluorescence showed IgG-positivity in 9(14.2%). C3 was positive in 27(42.8%). In LN cases, 47(51.09%) patients were women with Class IV lesions, which was the commonest group. Of the class IV patients (n=56) most presented with non-nephrotic range proteinuria (NNRP), while 35 (62.5%) had microscopic haematuria (MH) and 26(46.4%) showed elevated serum creatinine. All class II patients(n=15) were women (100%). 9 (60%) patients showed NNRP, 9 (60%) MH and 4(26.7%) elevated SC. All class III patients(n=5) were also women who had NNRP and MH. SC was elevated in 1(20%) patient. Conclusions: Most children and adults who underwent renal biopsy for ADPGN had presented with NS while a lesser number had NNMP. A study done by Wijewickrama et al. in 2015 also revealed that NS was the commonest presentation of ADPGN in adults. Common complications detected in our study were cellular crescents and tubular injury which were found more in patients with NNMP than NS. C3-positivity was commoner than IgG possibly because biopsies were performed during the latter phase of the disease. Common classes of LN were class IV, II and III. Most of these patients had NNRP and MH while a lesser number showed elevated serum creatinine.

OP0164 BLISS-LN: A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 3 TRIAL OF INTRAVENOUS BELIMUMAB IN PATIENTS WITH ACTIVE LUPUS NEPHRITIS

Background:Lupus nephritis (LN), a serious manifestation of systemic lupus erythematosus (SLE), affects nearly 70% of patients (pts) in high-risk groups. To preserve renal function, LN requires fast and effective treatment. Despite medical advances, progression rates at 15 years to end-stage renal disease (ESRD) remain >40% for pts with diffuse proliferative LN. Belimumab (BEL), approved in pts aged ≥5 years with active SLE, improved renal parameters in pts with baseline renal involvement in apost hocanalysis of Phase 3 trials data.Objectives:To assess efficacy and safety of intravenous (IV) BEL vs placebo (PBO), plus standard therapy (ST), in pts with active LN.Methods:BLISS-LN is a Phase 3, randomised, double-blind, PBO-controlled, 104-week study (GSK Study BEL114054,NCT01639339). Adults with SLE and biopsy-proven LN (class III, IV, and/or V) were randomised (1:1) to monthly BEL 10 mg/kg IV or PBO, plus ST. Primary endpoint: Primary Efficacy Renal Response (PERR); defined as urine protein creatinine ratio [uPCR] ≤0.7; estimated glomerular filtration rate [eGFR] within 20% of the pre-flare value or ≥60 ml/min/1.73m2; no rescue therapy) at Week (Wk) 104. Key secondary endpoints: Complete Renal Response (CRR; defined as uPCR <0.5; eGFR within 10% of the pre-flare value or ≥90 ml/min/1.73m2; no rescue therapy) at Wk 104; PERR at Wk 52; time to renal-related event (defined as ESRD/doubling of serum creatinine/renal worsening/renal disease-related treatment failure) or death. Other endpoints: time to PERR/CRR sustained through Wk 104; SLEDAI-S2K score <4 points at Wk 104; safety.Results:Overall, 448 pts were randomised (efficacy: 223/group; safety: 224/group). Significantly more BEL (43%) than PBO (32.3%) pts achieved PERR at Wk 104 (OR 1.55, 95% CI 1.04, 2.32; p=0.0311). More BEL than PBO pts achieved key secondary and other efficacy endpoints (Table).Overall, 214 (95.5%) BEL and 211 (94.2%) PBO pts had ≥1 adverse event (AE); 58 (25.9%) BEL and 67 (29.9%) PBO pts had ≥1 serious AE; 29 (12.9%) pts in each group had ≥1 AE resulting in study treatment discontinuation; 4 (1.8%) BEL and 3 (1.3%) PBO pts developed on-treatment fatal AEs.Conclusion:In the largest LN study to date, data from BLISS-LN demonstrate that BEL plus ST significantly improves LN renal responses compared with ST alone with a favourable safety profile.Study funding: GSK.Table.Endpoint, n (%)PBO(n=223)BEL(n=223)OR/HR (95% CI) vs PBOp-valueCRR at Wk 104*44 (19.7)67 (30.0)OR 1.74(1.11, 2.74)0.0167PERR at Wk 52*79 (35.4)104 (46.6)OR 1.59(1.06, 2.38)0.0245Time to PERR throughWk 104†72 (32.3)96 (43.0)HR 1.46(1.07, 1.98)0.0157Time to CRR throughWk 104†44 (19.7)67 (30.0)HR 1.58(1.08, 2.31)0.0189Time to renal-related event or death†63 (28.3)35 (15.7)HR 0.51(0.34, 0.77)0.0014SLEDAI-S2K score <4 points at Wk 104*41 (18.4)62 (27.8)OR 1.76(1.11, 2.78)0.0164*PBO and BEL columns represent the n (%) responders†Data presented as n (cumulative incidence)Disclosure of Interests:Richard Furie Grant/research support from: GSK, Consultant of: GSK, Brad H Rovin Grant/research support from: GSK, Consultant of: GSK, Frederic Houssiau Grant/research support from: UCB, Consultant of: GSK, Zahir Amoura Grant/research support from: GSK, Roche, Consultant of: GSK, Astra Zeneca, Amgen, Mittermayer Santiago: None declared, Gabriel Contreras Grant/research support from: Genentech, Merck, Consultant of: Genentech, Merck, Ana Malvar Consultant of: GSK and Roche, chi chiu mok: None declared, Amit Saxena Consultant of: GSK, AZ, BMS, Xueqing Yu: None declared, Y.K. Onno Teng Grant/research support from: GSK, Consultant of: GSK, Aurinia Pharmaceuticals, Novartis, Carly Barnett Shareholder of: GSK, Employee of: GSK, Susan Burriss Shareholder of: GSK, Employee of: GSK, Yulia Green Shareholder of: GSK, Employee of: GSK, Beulah Ji Shareholder of: GSK, Employee of: GSK, Christi Kleoudis Shareholder of: GSK, Consultant of: GSK, Employee of: Parexel, David Roth Shareholder of: GSK, Employee of: GSK

P0409CHARACTERISTICS AND OUTCOME OF ONE HUNDRED EGYPTIAN PATIENTS OF LUPUS NEPHRITIS: A SINGLE TERTIARY CARE CENTER STUDY

Abstract 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.

Long-term predictive value of acute kidney injury classification in diffuse proliferative lupus nephritis with acute kidney injury

BackgroundThe long-term predictive ability of acute kidney injury (AKI) classification based on “Kidney Disease: Improving Global Outcomes”(KDIGO) AKI diagnosis criteria has not been clinically validated in diffuse proliferative lupus nephritis (DPLN) patients with AKI. Our objective was to assess the long-term predictive value of KDIGO AKI classification in DPLN patients with AKI.MethodsRetrospective cohort study was conducted by reviewing medical records of biopsy-proven DPLN patients with AKI from the First Affiliated Hospital of Wenzhou Medical University between Jan 1, 2000 and Dec 31, 2014. Multivariate Cox regression and survival analysis were performed.ResultsOne hundred sixty-seven DPLN patients were enrolled,82(49%) patients were normal renal function (No AKI), 40(24%) patients entered AKI-1 stage (AKI-1), 26(16%) patients entered AKI-2 stage (AKI-2) and 19(16%) patients entered AKI-3 stage (AKI-3). The mean follow-up of all patients was 5.1 ± 3.8 years. The patient survival without ESRD of all patients was 86% at 5 years and 79% at 10 years. The patient survival rate without ESRD at 10 yr was 94.5% for No AKI patients, 81.8% for AKI-1 patients, 44.9% for AKI-2 patients and 14.6% for AKI-3 patients. The area under the ROC curve for KDIGO AKI classification to predict the primary end point was 0.83 (95% CI: 0.73–0.93) (P < 0.001). In Cox regression analysis, AKI stage was independently associated with primary endpoint, with an adjusted hazard ratio (HR) of 3.8(95% CI 2.1–6.7, P < 0.001).ConclusionSeverity of AKI based on KDIGO AKI category was associated with progression to ESRD in DPLN patients. Analytical data also confirmed the good discriminative power of the KDIGO AKI classification system for predicting long-term prognosis of DPLN patients with AKI.

Raised Plasma Levels of Asymmetric Dimethylarginine Are Associated with Pathological Type and Predict the Therapeutic Effect in Lupus Nephritis Patients Treated with Cyclophosphamide

Background: Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE). Asymmetric dimethylarginine (ADMA) has been associated with cardiovascular events in SLE patients and is a strong predictor of the progression of chronic kidney disease. However, whether ADMA can provide a predictive value for the diagnosis and treatment of LN patients remains unclear. This study evaluated the clinical significance of ADMA in LN patients. Methods: Blood samples of 114 patients with LN, 52 patients with primary glomerular disease, and 20 healthy people were collected. Plasma ADMA was measured via enzyme-linked immunosorbent assay. The relationship between plasma ADMA levels and pathological types and renal function and efficacy in LN patients were further analyzed. Results: There was no significant difference in plasma ADMA levels between LN and primary glomerular disease, but both were significantly higher than the values in healthy people (p < 0.05). Plasma ADMA levels in LN patients were negatively correlated with baseline estimated glomerular filtration rate (eGFR) and serum superoxide dismutase and positively correlated with serum cystatin C and serum β₂-microglobulin (p < 0.05). The plasma ADMA levels of diffuse proliferative LN patients were significantly higher than those of other histopathological classes of LN. High plasma ADMA levels in LN patients (OR = 1.012; 95% CI 1.003–1.022; p = 0.010) is a risk factor for diffuse proliferative LN. The area under the receiver operating characteristic (ROC) curve of diagnosing diffuse proliferative LN by plasma ADMA was 0.707 (95% CI 0.610–0.805). The area under the ROC curve of combination with plasma ADMA, serum complement C3, and eGFR for diffuse proliferative LN was 0.796 (95% CI 0.713–0.879), which was significantly higher than that of ADMA, complement C3, and eGFR for diffuse proliferative LN alone, respectively (p < 0.05). Low plasma ADMA is an independent protective factor for proliferative LN patients achieving complete remission with cyclophosphamide as induction therapy (OR = 0.978; 95% CI 0.961–0.996; p < 0.05). Conclusion: High plasma ADMA levels in combination with eGFR and complement C3 may be useful to diagnose diffuse proliferative LN. Low plasma ADMA may help to predict complete remission in proliferative LN patients treated with cyclophosphamide as induction therapy. Plasma ADMA may be a new biomarker to determine the pathological type of LN and predict the therapeutic effect.

Remission and long-term outcomes of proliferative lupus nephritis: retrospective study of 96 patients from Saudi Arabia.

Few data are available about the rate of short-term remission and its impact on the long-term outcomes of proliferative lupus nephritis in the Middle East. An observational study was carried out involving 96 adult patients with biopsy-proven focal or diffuse proliferative lupus nephritis (PLN) from four different hospitals. Data on induction, remission and long-term outcomes were collected and analyzed. Among the 96 patients with biopsy-proven PLN (median age 27 (IQR: 21,34) years, 85% women and median duration of systemic lupus erythematosus (SLE) prior to diagnosis 27 (IQR: 11, 55) months), 67% developed remission at 6 months (proportion 0.67; 95% CI 0.57, 0.76). Mycophenolate mofetil (MMF) was used in 45/96 (47%), CYC in 41/95 (43%) and other agents in 10/96 (10%). The choice of MMF as induction agent has increased in recent years. Among baseline characteristics, only histologic activity was found to have a significant association with remission, with active lesions more likely to remit than active/chronic and chronic lesions (AOR 6.5, 95% CI 1.44-29.39, p = 0.015). Based on Kaplan-Meier analysis, the 5-year renal survival rate without doubling serum creatinine was 73.8%. Compared to patients with complete remission, lower long-term renal survival rates were observed in patients with no remission (89.7 versus 43%, p = 0.001) and partial remission (89.7 versus 77.6%, p = 0.256). The cumulative rate of doubling serum creatinine, dialysis, relapse and death was 23%, 11%, 10% and 5%, respectively, at 48-month median follow up. Approximately two-thirds of patients with PLN develop remission in response to standard induction therapy. Remission was negatively associated with the presence of chronic changes in renal biopsy. Overall, MMF is the most commonly used agent to induce remission; however, with more severe disease CYC, is used more frequently. PLN is associated with significant long-term renal outcomes including a 26% cumulative rate of doubling of serum creatinine at 5 years. Initial remission predicts this long-term renal survival.

Consecutive Spontaneous Triplet and Twin Pregnancies in a Woman After Renal Transplantation

BackgroundThere are numerous reports of successful pregnancies following kidney transplantation. However, little information is available regarding the management and evolution of multiple pregnancies in a kidney-transplanted woman. Case reportWe report the case of successful consecutive spontaneous triplet and twin pregnancies in a woman who had undergone kidney transplantation at 30 years of age, 12 years before the first pregnancy, as a result of end-stage renal disease secondary to chronic glomerulonephritis due to diffuse proliferative lupus nephritis. An integrated multidisciplinary team closely followed progress during the pregnancies. Maternal complications during the pregnancies included light proteinuria, controlled hypertension, and anemia. No graft rejection episodes or deterioration of renal function was noted during the pregnancies or after the deliveries. ConclusionCurrently, more than 2 years after her last pregnancy, the mother and all 5 babies are healthy and the mother’s renal transplant function is normal.

Annals for Educators - 19 February 2019.

Annals for Educators - 19 February 2019.