Nephrotic Proteinuria Research Articles

Clinical Characteristics and Histopathology in Adults With Focal Segmental Glomerulosclerosis

Rationale & ObjectiveFew data are available regarding histological features at the time of focal segmental glomerulosclerosis (FSGS) diagnosis among diverse real-world populations. This study describes clinical and histological characteristics, and correlates of histological disease severity, in adults with FSGS who underwent a clinical kidney biopsy. Study DesignReal-world cohort study with data derived from health records. Setting& Participants: Adults with FSGS by kidney biopsies from Arkana Laboratories during 1 January 2016 to 31 May 2020. ExposuresRace, CKD stage, nephrotic proteinuria, age, sex, and hypertension. OutcomesSevere histological disease, defined as global glomerulosclerosis in >50% of glomeruli and >25% interstitial fibrosis and tubular atrophy (IFTA). Analytical ApproachDemographic, clinical, and histological characteristics were compared between race groups. Correlates of severe disease were analyzed by multiple logistic regression. ResultsAmong 2,011 patients with FSGS, 40.6% were White and 23.6% Black. White patients were older (52.8 versus 45.5 years, P < 0.001) with higher estimated glomerular filtration rate (eGFR) than Black patients (53.5 versus 43.1 ml/min/1.73 m2, P < 0.001). A higher proportion of Black patients had global glomerulosclerosis ≥50% (32.1% versus 14.6%, P < 0.001) or IFTA >50% (34.6% versus 14.7%, P < 0.001). Severe histological disease was more likely in Black patients (odds ratio 2.46; 95% confidence interval 1.59, 3.79; P < 0.001). A higher proportion of patients with nephrotic than non-nephrotic proteinuria exhibited diffuse foot process effacement. LimitationsUnequal representation across United States (US) regions, missing demographic and clinical data, and lack of data on primary versus secondary FSGS, treatments, or outcomes. ConclusionsBlack patients were more frequently diagnosed at younger age with lower eGFR and more severe histological disease compared with White patients. Timelier identification of FSGS could increase the opportunity for therapeutic intervention, especially for high-risk patients, to mitigate disease progression and complications.

Rare Case of Dense Deposition Disease with Combined C3 and C4d Deposits with MYH9-related Mutation

Background: The C3 glomerulopathies are a group of rare forms of glomerulonephritis with an incidence of 1-2 cases per million. It is mainly characterized by dysregulation of the alternative complement pathway. It is further classified morphologically based on electron microscopy ultrastructural findings into Dense Deposition Disease (DDD) and C3 glomerulonephritis. DDD is normally characterised by C3 Deposits. Case: We report a rare case of a young Emirati male who presented with sub nephrotic proteinuria and microscopic haematuria on routine evaluation. Renal biopsy showed features of DDD with combined C3 and C4 deposits. The retinal evaluation showed features of Drusen classically seen in DDD. Genomic study showed heterozygous mutation in c.5842G&gt;C (p.Asp1948His) variant of uncertain significance in MYH9 gene. Discussion: C3 Glomerulopathy is a type of immune mediated disease previously classified as membranoproliferative glomerulonephritis. DDD is mainly characterised by C3 deposits in the glomerular basement Membrane. Our case has both C3 and C4d deposits, which is a rare entity. It shows the activation of both classical and alternate pathways. Conclusion: Dense deposition disease is a rare complement mediated glomerulopathy. It is characterised by C3 deposits. Dense deposition disease with combined C3 and C4d deposits is a new entity. The treatment and prognosis of such cases will be different and unique compared to the normal cases of DDD.

Abstract 15484: Heart Transplantation in a Light-Chain Amyloidosis Patient at Mayo Stage IIIa After Anti-Plasma Cell Chemotherapy With Complete Remission

A 42-year-old female patient was admitted for lower limb edema. Laboratory tests showed nephrotic proteinuria (2.76g/24h). Serum-free λ light chains were 84.9 mg/L, with a κ/λ ratio of 0.12. Bone marrow examination detected 6% immature clonal plasma cells. Amyloid deposition was identified in a renal biopsy. Cardiac magnetic resonance (CMR) revealed normal left ventricular ejection fraction (LVEF), left ventricular circumferential late gadolinium enhancement (LGE), and elevated myocardial T1 value (1459ms) and extracellular volume (47.4%). She was diagnosed with AL amyloidosis and classed as IIIa by the Mayo Stage 2004. A hematologic complete response (CR) was achieved and sustained after treatment with sequencing cyclophosphamide, bortezomib, dexamethasone (CyBorD) and daratumumab regimen. The follow-up CMRs were underwent at 6, 12, and 18 months after starting chemotherapy, which monitored cardiac changes in reponse to CR. Unfortunately, there was no alleviation of cardiac involvement. CMR re-examination (at 42 months) revealed severe cardiac function impairment (LVEF 28%), and dramatically increased extracellular volume (66.2%). Then, she underwent heart transplantation (HTx) evaluated by the heart transplantation multidisciplinary team. Three months later, she was doing well, CMR demonstrated stable cardiac allograft function. Repeated endomyocardial biopsies showed no amyloid deposits. This case illustrates that cardiac amyloid deposition might be a dynamic process in AL amyloidosis and highlights the value of CMR in long-term monitoring and identifying the patients reached CR who need HTx.

Monogenic Causes Identified in 23.68% of Children with Steroid-Resistant Nephrotic Syndrome: A Single-Centre Study

Introduction: Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of end-stage kidney disease in children, mostly associated with focal segmental glomerulosclerosis (FSGS). Advances in genomic science have enabled the identification of causative variants in 20–30% of SRNS patients. Methods: We used whole exome sequencing to explore the genetic causes of SRNS in children. Totally, 101 patients with SRNS and 13 patients with nephrotic proteinuria and FSGS were retrospectively enrolled in our hospital between 2018 and 2022. For the known monogenic causes analysis, we generated a known SRNS gene list of 71 genes through reviewing the OMIM database and literature. Results: Causative variants were identified in 23.68% of our cohort, and the most frequently mutated genes in our cohort were WT1 (7/27), NPHS1 (3/27), ADCK4 (3/27), and ANLN (2/27). Five patients carried variants in phenocopy genes, including MYH9, MAFB, TTC21B, AGRN, and FAT4. The variant detection rate was the highest in the two subtype groups with congenital nephrotic syndrome and syndromic SRNS. In total, 68.75% of variants we identified were novel and have not been previously reported in the literature. Conclusion: Comprehensive genetic analysis is key to realizing the clinical benefits of a genetic diagnosis. We suggest that all children with SRNS undergo genetic testing, especially those with early-onset and extrarenal phenotypes.

Assessing the Accuracy of Diagnostic Tests to Quantify Proteinuria in Nephrotic Children: A Cross-Sectional Study

Objective: To assess the diagnostic accuracy of 24-hour proteinuria estimation and urine dipstick-taking spot urine protein creatinine ratio as the gold standard in children with steroid-sensitive nephrotic syndrome. Study Design: Cross-sectional analytical study. Place and Duration of Study: Department of Paediatric Nephrology, Sindh Institute of Urology and Transplantation, Karachi Pakistan, from Oct 2020 to Mar 2021. Methodology: Proteinuric children were enrolled to quantify proteinuria by 24-hour urine protein estimation, spot urine protein creatinine ratio and urine dipstick. Sensitivity analysis was performed, and receiver operating curves were plotted to assess the diagnostic accuracies of 24-hour proteinuria and urine dipstick against spot urinary protein creatinine ratio. Scatter plots compared the correlation of serum albumin and cholesterol with 24-hour urine protein estimation and spot urine protein creatinine ratio. Results: Forty-two children with a median age of 8 years (IQR 6–10) were included. Nephrotic range proteinuria was detected in 39(93%) children with spot ratio, 16(38%) cases using 24-hour proteinuria estimation and 50% with a urine dipstick.Twenty-four-hour protein estimation showed a sensitivity of 63.4%, and urine dipstick had a sensitivity of 53.8% in detecting nephrotic range proteinuria compared to spot ratio with a negative predictive value of 6.3% and 14.3%, respectively.Hypoalbuminemia and cholesterol correlated better with spot ratio than 24-hour proteinuria with r- values 0.0143 and 0.0713, respectively. Conclusion: Twenty-four-hour urine protein estimation and dipstick correlate with spot urine protein creatinine ratio in detecting nephrotic proteinuria with no statistical difference in diagnostic accuracy.

Experience with abatacept in refractory lupus nephritis.

Lupus nephritis is a major cause of morbidity in patients with systemic lupus erythematosus. Responsiveness to treatment is crucial to avoid chronic kidney disease. New molecules have been developed in recent years to improve renal survival rates. Biological therapies as coadjutant to conventional induction treatment have been tested in randomized clinical trials with heterogeneous results. Like many others biologic therapies, Abatacept has not shown a clear benefit in the context of clinical trials. We present two cases of lupus nephritis patients in whom addition of abatacept resulted in complete remission of the renal disease. The first case described a 49-year-old male with class IV lupus nephritis with nephrotic range proteinuria and high immunological activity refractory to conventional treatment with cyclophosphamide and corticosteroids and multitarget therapy with tacrolimus, mycophenolate mofetil and prednisone. Several biological therapies (rituximab, belimumab and tocilizumab) were unsuccessfully tried, so that abatacept was added to his background multitarget therapy showing complete clinical response. The second case described a 52-year-old female with class IV lupus nephritis treated initially with conventional treatment with partial response. In successive renal flares with nephrotic proteinuria, she showed intolerance to rituximab and refractoriness to voclosporin. Finally, abatacept was added to her background therapy with MMF and PDN showing complete and maintained remission of the disease. In no case the use of abatacept was associated with serious adverse events. Based on our experience, abatacept should be considered as a safe rescue therapy in patients with refractory lupus nephritis and proteinuria with nephrotic range. In addition to this case, we reviewed the use of abatacept in lupus nephritis in the literature.

Outcomes of minimal change disease without nephrotic range proteinuria.

Minimal change disease (MCD) is characterized by edema and nephrotic range proteinuria (NS). However, the fate of MCD without nephrotic proteinuria requires elucidation. We retrospectively reviewed 79 adults diagnosed with primary MCD at their initial renal biopsy at a tertiary hospital between May 2003 and June 2017. Clinicopathologic features were compared between patients with and without NS. The frequency of flaring to nephrotic proteinuria and renal outcomes were assessed during follow-up. There were 20 and 59 patients in the Non-NS and NS groups, respectively. The Non-NS group had a lower frequency of acute kidney injury (AKI) during the follow-up period [5.0% vs. 59.3%, p <0.001]. The response rate to steroid treatment was 100% in the Non-NS group and 92.3% in the NS group (p = 1.000). Except for one patient, the Non-NS group was treated with steroids when their proteinuria increased to a nephrotic level. There were no differences in the frequency of the first relapse or the number of relapses among patients with initial remission from nephrotic range proteinuria. At the final visit, the complete remission rate was 73.4%. The estimated glomerular filtration rate during follow-up was significantly better in the NS group than the Non-NS group, given the higher rates of AKI at renal biopsy. The rates of renal events, end-stage renal disease, and mortality did not differ between the groups. Adult MCD patients with nephrotic and non-nephrotic range proteinuria showed similar outcomes. Accordingly, this population must be carefully managed, regardless of the amount of proteinuria at renal biopsy.

#5201 KIDNEY BIOPSY IN PATIENTS WITH TYPE 2 DIABETES: A SINGLE CENTER OBSERVATIONAL STUDY

Abstract Background and Aims Patients with type 2 diabetes mellitus (T2DM), may have various underlying causes contributing to kidney disease beyond diabetic nephropathy (DN). In such cases, a kidney biopsy (KB) can provide a definite diagnosis and allow for tailored treatment options. The aim of this study is to evaluate non diabetic kidney disease (NDKD) in T2DM patients and identify data to support KB indications. Method This is a retrospective observational study that included patients with T2DM who were submitted to a native KB between 2011 and 2022. We collected demographic, clinical and laboratory data at the date of biopsy. KB indication was considered in order to include the patients in the first encountered criteria defined sequentially as the presence of (1) nephrotic syndrome, (2) low or rapidly declining estimated glomerular filtration rate (eGFR), (3) nephrotic proteinuria and (4) hematuria. Results We analysed 72 patients with T2DM that were submitted to KB (Table 1). All except one patient had hypertension and 38 patients were screened for diabetic retinopathy (DR), which was present in 23 patients (60%). The criteria for KB was in most of the patients (59.7%) a low or rapidly declining eGFR, followed by nephrotic proteinuria (19.4%), nephrotic syndrome (16.7%) and hematuria (4.2%). KB showed 50% (n = 36) of patients with NDKD, 12.5% (n = 9) with NDKD and DKD and 37.5% (n = 27) with isolated NDKD. Among these patients, hypertensive nephrosclerosis (19.4%), focal segmental glomerulosclerosis (13.8%), acute interstitial nephritis (13.8%), membranous nephropathy (11.2%) and IgA nephropathy (5.6%), were the most prevalent diagnosis. Patients with DR had a higher prevalence of DKD with a positive predictive value (PPV) of 87%. On the other hand, in the absence of DR, DKD was only absent in 66.7%. Patients submitted to KB for the criteria of low or rapid declining eGFR had significantly more NDKD (p = 0.016). DKD with or without NDKD was found in patients with higher levels of albumin to creatinine ratio (p = 0.001) and HbA1c (p = 0.05). Conclusion Our data showed that NDKD is prevalent in T2DM patients, and given its potentially treatable nature, KB should be considered in T2DM patients, especially in those with low or rapid declining eGFR. DR supports the diagnosis of DKD (PPV of 87%), but alone is insufficient to exclude other causes. Patients with DKD had higher levels of albuminuria and HbA1c. Overall, more than half of the patients had hematuria, without any correlation with any group.

#5132 POST-COVID-19 ANTI-GLOMERULAR BASEMENT MEMBRANE DISEASE: TWO CLINICAL CASES

Abstract Background and Aims Acute kidney injury is a common complication in patients hospitalized with COVID-19, has multiple aetiologies, and is usually multifactorial. We present two cases of anti-glomerular basement membrane (anti-GBM) disease diagnosed after SARS-CoV-2 infection, suggesting a causal correlation. Case Reports A 76-year-old female, with chronic kidney disease (serum creatinine 1.5mg/dL), hypertension, weight loss (16 Kg/6 months) and a pancreatic nodule under surveillance, presented to the emergency department with 1 week of nausea, vomits, diarrhoea and oliguria, as well as a history of mild SARS-CoV-2 infection 2 weeks before presentation. Lab work revealed severe anaemia (7.4 g/dL), inflammatory markers elevation, nephrotic proteinuria (proteinuria/creatininuria ratio 30 g/g), leucoerythrocyturia, serum creatinine of 19.3 mg/dL, hyperkalaemia and metabolic acidosis requiring dialysis induction. Renal ultrasound showed signs of chronicity and several cysts. Aetiological study disclosed positive anti-GBM antibody (1800 U/L) and negative ANCA. Complementary study failed to identify pulmonary involvement or neoplasms. Given the severity of the renal dysfunction along with the absence of alveolar haemorrhage, immunosuppression and plasmapheresis were not initiated. Patient was discharged and remains dialysis dependent. A 65-year-old male smoker with type 2 diabetes and combined pulmonary fibrosis and emphysema, presented in the emergency department with 2 months of asthenia, weight loss and anaemia, in addition to dyspnoea and haemoptysis in the past 3 days. Lab work exposed moderate anaemia (9.7 g/dL), elevated inflammatory markers, serum creatinine of 1.18 mg/dL (previously 0.8 mg/dL), leucoerythrocyturia and positive SARS-CoV-2 test. Angio-Computed Tomography exhibited known pulmonary fibrosis and possible bacterial superinfection. Despite antibiotic therapy (10 days of levofloxacin), haemoptysis remained and kidney function continuously worsened (serum creatinine 2.1 mg/dL). Complementary study showed positive ANCA-MPO (1125.4 U/L) and anti-GBM antibody (460.8U/L). Renal ultrasound was innocent. Kidney biopsy revealed: 6 glomeruli with cellular crescents with segmental necrosis, 3 with focal Bowman's capsule rupture; erythrocyte casts; intimal arterial fibrosis; moderate tubular atrophy; diffuse linear deposits of IgG. Immunosuppression was initiated with prednisolone (1 mg/Kg/day), cyclophosphamide (3x 12.5mg/Kg-750 mg, 2x 500 mg), rituximab (2x 1g), immunoglobulin (1x 2 g/Kg) and plasmapheresis (15 sessions). Kidney function continued to deteriorate (maximum serum urea 306 mg/dL, maximum serum creatinine 6.92 mg/dL) requiring dialysis induction 3 weeks after the beginning of immunosuppression. Even though haemoptysis ceased, the patient remains dialysis dependent 8 months after. Conclusion Literature reports an increase of Anti-GBM disease since the beginning of the pandemic. The presented cases support the apparent correlation, suggesting SARS-CoV-2 as a precipitant of this disease by endothelial injury with basal membrane exposure and autoantibody development. In the second case, the authors assume a subacute ANCA-MPO vasculitis with superimposed anti-GBM (eventually precipitated by COVID-19). Even though the causal association is not established, we highlight the importance of clinical suspicion of this rare aetiology in cases of acute kidney injury after SARS-CoV-2 infection.

#5710 CHARACTERIZATION OF RESPONSE TO TREATMENT WITH RITUXIMAB IN PATIENTS WITH PRIMARY GLOMERULOPATIES

Abstract Background and Aims Rituximab (RTX) is an anti-CD20 monoclonal antibody used in renal diseases with glomerular involvement, which usually present with proteinuria. The doses used in this pathologies are extrapolated from other diseases such as rheumatoid arthritis, but the optimal regimen in this population has not been well defined. Objective To describe the behaviuor of RITUXIMAB in patients with primary glomerulopathies in whom its use is indicated. Method Descriptive low-intervention single-center clinical trial approved by the Spanish Medicines Agency (NEFRTX, EUDRACT 2020-000484-23. Patients treated with rituximab were included according to medical criteria, prior approval by the Pharmacy Commission. The regimen used was 1g every 15 days, or only 1gr dose with premedication according to clinical practice guidelines. 24-hour blood and urine samples were collected on days 1 (post-rituximab), 7, 15 (pre and post-rituximab), 28, and 45. Serum rituximab was determined using ELISA (Lisa-Traker®-Rituximab, Theraradiag®). Clinical and pharmacokinetic data analyzes were performed considering a single compartment model by non-linear regression with Winnolin® to obtain clearance (Cl), half-life (t1/2), maximum concentration (Cmax) and volume of distribution (Vd). Some quantitative results are expressed as mean ± standard deviation. Linear regression was used to establish correlations. Results The results of 5 patients were analyzed, 2 women and 3 men, with a mean age of 68.8 ± 17.02 years of 72 years and a diagnosis of membranous GN (3), ANCA MPO GN (1), focal and segmental GN (1). Renal function CKD EPI: GFR between 45- 60 ml/min N = 2 GFR &amp;gt;60 ml/min N = 3. According to clinical practice guidelines, patients received 1g doses, 2/5 patients received a second dose on day 15. The evaluation parameters were: proteinuria, CD 19+ lymphocyte depletion, Antibodies titers and histological characteristics as appropriate. levels of rituximab in urine samples after the rituximab administration (15, 30, 180, 365 days after) were determinate. All the patients presented proteinuria, with a mean of 11±14.6 g in 24 h urine. Mean Rituximab clearance was 0.676±0.431 ml/h/kg, distribution volume was 222.35±140.52 mL/Kg and Cmax 69.66±26.14 mcg/mL and t1/2 269.66± 229.71 h (11 days approximately). There is a correlation between proteinuria and rituximab half-life (p = 0.077), as well as between proteinuria and clearance creatinine (p = 0.975) suggesting that half life of rituximab is lower if proteinuria increases (Fig. 1). All presented lymphocyte depletion of CD 19 at 45 days. However, those with more proteinuria &amp;gt;2.5 g (N = 3) in those 45 days, after 6 months of exposure to RTX, progressive repopulation of CD19 was observed, which persisted in the year of follow-up. Conclusion In patients with high proteinuria, rituximab has a t1/2 lower than the 21–28 days described in the data sheet, which may suggest that patients with nephrotic syndrome may require higher doses to ensure the effectiveness of treatment with rituximab. Repopulation of CD19 in 45 days could be a reliable indicator of non response in patients with nephrotic proteinuria.

#6407 RENAL LIMITED VASCULITIS: DATA FROM A CROATION REFERRAL CENTER

Abstract Background and Aims Small vessel vasculitis and in particular ANCA associated vasculitis (AAV) are diseases with variable clinical presentation. Renal limited vasculitis (RLV) can vary in presentation and characteristics compared to systemic disease. There is a tendency to categorise RLV as a part of microscopic polyangiitis (MPA) spectrum though there seem to be differences in terms of both histology and serology between RLV and MPA. We present data on patients with renal limited vasculitis from our referral center. Method This study included 106 consecutive AAV patients with biopsy proven renal involvement in the period from 2007-2017. Category variables were analysed with Fisher Exact testom and continuous with Kruskal-Wallis testom. Statistical difference was then analysed posthoc with Chi-square test. Kaplan Meyer survival analysis and multivariate Cox proportional hazard regression analysis were used to explore difference between clinical phenotypes and finding significant predictors regarding outcomes which were defined as combined outcome end-stage renal disease and death (ESRDD), ESRD alone, the death outcome alone and relapse rate. Results Out of 106 AAV patients with renal involvement in our database: 66 (61,1%) MPA, 20 (18,5%) GPA (granulomatosis with polyangiitis), 20 (18,5%) RLV. In RLV group 14 (70%) were female and average age was 55 (IQR 47-60). Average SCr in RLV group was 234 μmol/l (IQR 168-376,5) and median proteinuria was 3,3g/24h (IQR 0,9-3,8) and most of these patients presented with either nephrotic syndrome (30%) or RPGN (30%). Serologicaly 90% of RLV patients were ANCA negative and 10% were MPO-ANCA positive. Histologicaly (Berden classification) 60% had mixed class, 25% crescentic, 10% focal and 1% sclerotic. Average BVAS score was 14 (IQR 12-17). Compared to MPA and GPA, RLV patients were younger (p=0,058), had less expressed constitutional symptoms (p= 0,013) with lower average BVAS (p=0,0001) and lower CRP levels (p=0,001). Though there was no significant difference of average SCr level RLV patients presented more often with nephrotic syndrome (p=0,014), had histological predominantly mixed class (p=0,006) and higher interstitial fibrosis and tubular atrophy (IFTA) percentage (p=0,086). Interestingly, compared to MPA and GPA majority of RLV patients were ANCA negative (p=0,001). There were no statistically significant differences in treatment used both in induction (including need for dialysis and/or PLEX) or remission maintenance treatment between RLV, MPO and GPA group. In survival analysis there was no statistical differences for all of the outcomes between RLV group, MPA and GPA group. Conclusion RLV can be challenging disease considering it's clinical presentation but also characteristics of renal involvement in terms of more often nephrotic proteinuria and higher IFTA percentage. This might suggest that these patients could have slower disease course (so called slower progressors). Also interestingly in our cohort most of these patients were ANCA negative which also makes diagnosis predominantly a combination of clinical presentation and histology thus prompting a question of how should we classify RLV within a spectrum of small vessel vasculitis. More research is needed to better understand the RLV.

Systemic lupus erythematosus presenting as lupus erythematosus tumidus and lupus nephritis: a case report

BackgroundLupus nephritis and lupus erythematosus tumidus (LET) are uncommon manifestations of systemic lupus erythematosus (SLE), and their coexistence as the initial presentation of SLE is exceedingly rare. Here, we report such a case, emphasizing the diagnostic challenges and therapeutic implications of this unusual association.Case reportA 38-year-old North African woman presented in Nephrology department with a history of lower extremity edema, fatigue, and weight loss of 3 kg in 4 weeks. Physical examination revealed LET lesions on the chest and the Neck. Laboratory investigations showed lymphopenia, low C3 and C4 complement levels, positive antinuclear antibodies, anti-dsDNA antibodies, and anti-SSA/Ro antibodies. Renal function tests showed normal serum creatinine and nephrotic proteinuria. Renal biopsy revealed Class V lupus nephritis. Skin biopsy confirmed the diagnosis of LET, with the presence of lymphohistiocytic infiltrates and dermal mucin. The patient was diagnosed with SLE based on the 2019 EULAR/ACR criteria and treated with prednisone (1 mg/kg/day) and hydroxychloroquine. She showed significant improvement in her cutaneous and renal symptoms at 6 and 12 months follow-up.ConclusionThe rarity of the coexistence of LET and lupus nephritis as the initial manifestation of SLE, especially in the North African population, underscores the need for further research to elucidate the immunopathogenic mechanisms and prognostic factors associated with this association.

#6213 RISK FACTORS FOR END-STAGE RENAL DISEASE IN IGA NEPHROPATHY

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular nephropathy worldwide and one of the principal causes of chronic kidney disease. The presentation of this nephropathy is different between ethnic groups. The aim of our work is to describe the clinical, biological, and pathological symptoms of maghrebian patients diagnosed with IgAN. Method We conducted a retrospective descriptive study over 46 years from 1975 and 2021. This study included 213 patients with renal biopsy-proven IgAN whose clinical, biological, and pathological data were assessed and classified according to the Oxford classification. Results The mean age of the patients was 34.48 [15-80] with male predominance (sex ratio=1.77). Thirty-nine patients had a family history of kidney disease. 109 patients (51%) had hypertension. The median proteinuria was 2.6 g/24 h [0-46.17 g/24 h]. Nephrotic proteinuria(&amp;gt;3 g/24h) was found in 98 patients (46%). The initial median glomerular filtration rate was 33.9 ml/min/1,73 m²SC. At the end of the follow-up, it was 23.7 ml/min/1.73 m²SC. Renal biopsy was performed in all the cases. The lesions observed in optical microscopy were mesangial proliferation M1 (63.8%), endocapillary proliferation E1(8.5%), glomerulosclerosis S1 (71.4%), interstitial fibrosis or tubular atrophy T1-T2 (72.8%) and crescents C1 (16.9%). Fifty-two percent of the patients were treated with ACE inhibitors or ARAII.47.9% of our population reached end-stage kidney disease and required dialysis. Only 23 patients (10.8%) had a kidney transplant. Conclusion The treatment of IgA nephropathy is based on early diagnosis, hence the need for a screening strategy to prevent the discovery of this nephropathy in an advanced stage.

#5722 NEW ONSET OR RECURRENT GLOMERULONEPHRITIS FOLLOWING SARS-CoV2 VACCINATION: A MULTICENTER EXPERIENCE

Abstract Background and Aims In general, vaccination is a well-known trigger for the onset or recurrence of glomerulonephritis or more in general autoimmune disease. Starting from the beginning of 2021 millions of people worldwide have received a vaccination of SARS-CoV2. Over the months, several cases of glomerulonephritis with a clear temporal association with the vaccination have been described [1,2]. Method To better understand the characteristics, pattern of presentation, temporal and qualitative association with SARS-CoV2 vaccination and outcome, we designed a retrospective, multicenter, nationwide study aimed at collecting information on new onset or recurrence of primary or secondary vaccination following SARS-CoV2 infection. We present the preliminary findings from the first seven participating centers that completed data collection. For inclusion patients needed to be ≥16 years, have either a biopsy-proven glomerulonephritis or gross haematuria without urological explanation in close relationship with the vaccine. For outcome definition, partial remission was proteinuria &amp;gt;300 mg/day, complete remission proteinuria 300–3500 g/day. Results We report 57 cases (M/F 22/35, mean age 48.59±18.99 years, median follow-up of 11.8 months (min 1.1, max 22.5). Of these, 25 (44%) were new onset glomerulonephritis, the remaining 32 (56%) were recurrence of already known cases (1/3 in complete remission, 2/3 in partial remission). Table 1 summarises the diagnosis new-onset or recurrent glomerulonephritis. 37 (65%) were primary glomerulonephritis, the other 20 (35%) kidney involvement of systemic diseases. The most frequent diagnosis was IgA nephropathy (IgAN, n = 17, 30%), followed by lupus nephritis (n = 9, 16%) and membranous nephropathy (n = 7, 12%). Compared to recurrence, patients with new-onset glomerulonephritis had a higher prevalence of minimal change disease (4 vs 1 case), Henoch Shoenlein purpura (3 vs 0) and FSGS (2 vs 0). Conversely, in patients with recurrence, we observed a higher rate of IgAN (14 vs 3), microscopic polyangiitis (5 vs 1) and lupus nephritis (7 vs 2). Most of the cases occurred following an mRNA vaccine (n = 42, 90%). The median time of onset was of 18 days. The onset was related more to the second dose of vaccine (n = 27, 47.4%), followed by the first dose (n = 14, 25%) and then the third dose (n = 12, 21.1%), with an imbalance between new-onset vs recurrence (C2, 11.18; p = 0.011) Fig. 1). The information is missing in 4 cases. Most of the patients presented with nephrotic proteinuria (n = 24, 42%). Following treatment, 15 (26.3%) patients obtained partial remission, 18 (31.6%) had complete remission and the remaining 21 (36.8%) had no response. The information is missing for 3 patients. Conclusion Following SARS-CoV2 vaccine, de novo or recurrent glomerulonephritis can occur. The majority of the cases were related to mRNA vaccines. However, the vaccine policy in Italy could have influenced this finding.

#5124 GENETIC GLOMERULAR DISEASES IN THE ADULT PATIENT: A WORK IN PROGRESS – SINGLE CENTRE COHORT

Abstract Background and Aims Recent advances in genetic molecular techniques have allowed the expansion of knowledge in glomerular diseases of genetic cause, including the identification of genes involved in focal and segmental glomerular sclerosis (FSGS). The prevalence of adult-onset genetic FSGS varies widely depending on the population studied. In central Europe, NPHS2 and COL4A3, COL4A4 e COL4A5 genes are postulated to be the most frequent genes implicated in genetic causes of adult FSGS. This study aims to characterize patients submitted to genetic study of glomerular diseases in the Nephrogenetics Clinic of our centre. Method We conducted a single-centre retrospective analysis of the patients submitted to genetic study of glomerular diseases in the Nephrogenetics Clinic of our centre from 2016 to 2022. Adult patients with a glomerular disease phenotype suggestive of a genetic cause were studied, using a predetermined phenotype-targeted panel of genes, through massive parallel sequencing. The number of genes included in this panel has increased (from 21 genes in 2016 to 49 genes since 2018); given this change, patients with a negative result on the first approach repeated screening with the broader panel. Additionally, patients presenting with advanced chronic kidney disease (CKD) without an identifiable phenotype, studied with a larger panel for CKD causing genes, are reported. In patients with a negative result but highly suggestive presentation, whole exome sequencing (WES) was considered, after multidisciplinary discussion with a Geneticist's evaluation. Patients with variants of unknown significance (VUS) were referred to a Genetics’ consultation for genetic counselling and segregation studies. Results Of the 80 patients studied (comprising 74 families), 52.5% were female (n=42) and 79% (n=63) of Caucasian ascent. Mean age was 45.4 ± 16.0 years. Nine patients were studied with the larger gene panel for CKD. 85% (n=68) had CKD (all stages) at presentation, with proteinuria (ranging from sub-nephrotic to nephrotic range) and 15% had asymptomatic urinary changes. 50% (n=40) of patients had positive family history, and 31% (n=25) had a syndromic presentation and/or extra renal manifestations. 27.5% (n=22) had a renal biopsy, and the most prevalent result was FSGS (11%; n=9). Genetic variants were identified in 70% (n=56) of the patients; but pathogenicity is not fully established in all: genotype-phenotype correlations, including inheritance pattern and histological correlation, and segregation studies (when indicated and possible) are ongoing. In 5 patients results are pending. Pathogenic / likely pathogenic variants were identified in at least 47.5% (n=38) patients. The most frequently implicated genes were: COL4A3, COL4A4 e COL4A5 (n=21), high risk APOL1 (n=8); NPSH2 (n=5), IFN2 (n=6, 3 pathogenic, 1 variant of unknown significance (VUS), 2 under segregation studies) and MYH9 (n=3). COL4A3, COL4A4 e COL4A5 mutations occur with Alport syndrome, but also with histologically documented FSGS, sub-nephrotic and nephrotic proteinuria, nephrotic syndrome and asymptomatic urinary changes. In our cohort, NPHS2 p.R229Q was identified in 5 patients (6%), but only with pathogenic significance in 3 patients, and APOL1 high risk haplotype was co-identified with COL4 variants in 3 patients. Conclusion The genetic study of a cohort of patients suspected of genetic FSGS allowed the identification of genetic variants in the genes of interest in a high percentage of cases. The most frequently implicated genes were COL4A3, COL4A4 e COL4A5, NPHS2, INF2 and APOL1 high risk haplotype. The high percentage of gene variants identified in our cohort is probably due to the selection of a population with a high likelihood of genetic FSGS. Further studies will clarify the causal and/or modifier effect of some genes, namely COL4A3, COL4A4 e COL4A5. The future use of WES in cases of high likelihood of genetic cause will probably allow the identification on novel candidate genes and increase the clinical benefits of a genetic diagnosis of FSGS.

#3476 CHARACTERISTICS AND SURVIVAL DATA OF PATIENTS WITH PRIMARY FOCAL SEGMENTAL SEGMENTAL GLOMERULOSCLEROSIS: TSN-GOLD MULTI-CENTER STUDY

Abstract Background and Aims We aimed to investigate the characteristics and survival data of biopsy-proven primary focal segmental glomerulosclerosis (FSGS) in adult patients across Turkey. Method Patients with primary FSGS were included by retrospectively scanning the database of the Turkish Society of Nephrology Glomerular Diseases Study Group (TSN-GOLD). Demographic and laboratory data of the patients at baseline, sixth month, first year, and third year were recorded. Patients with secondary FSGS, missing data were excluded. Results The study included 1668 patients with primary FSGS who met the criteria. 1386 patients were included. The mean age of the patients was 41.16±13.88 years, and 712 patients (51.4%) were male. The total follow-up period from the biopsy date was 37.63±40.45 (IQR:1-249) months. The mean blood pressure of the patients, respectively; 130.43±17.63/81.47±10.85 mmHg, serum creatinine 1.29±1.28 mg/dl, e-GFR: 86.10±42.70 ml/min/1.73 m2, serum albumin: 3.41±0.92 g/dl and proteinuria amount was 4687±4658 g/day. Microscopic hematuria was detected in 40.2% of the patients. The rate of admission with nephrotic syndrome was .45.7%. In light microscopy, the mean glomeruli count was 17.36±10.58, with 3.32±4.08 global sclerosis and 0.08±065 glomeruli had segmental sclerosis. Mesangial proliferation was found in 53.1% of the patients and interstitial inflammation was found in 69.7% of the patients. Interestingly, the most common immunoglobulin staining was IgM (19.3%) in the immunofluorescent microscope. The rate of receiving immunosuppressive therapy was 36%. A positive correlation was found in terms of serum creatinine, albumin, and proteinuria in the 3-year follow-up (p&amp;lt;0.001). In the univariate analysis, the group with e-GFR&amp;lt;60 ml/min/1.73 m2 was older, hypertensive, uremic, anemic, had more interstitial fibrosis/tubular atrophy and less interstitial inflammation and mesangial proliferation (p&amp;lt;0.001). In terms of quantitative proteinuria, Patients with proteinuria &amp;gt;3.5 g/day were more hypertensive, hyperlipidemic, hypoalbuminemic and anemic (p&amp;lt;0.05). Conclusion Our study presented important data on the status of patients with national primary FSGS. Approximately one-third of patients receive immunosuppressive therapy. The most important factors determining the prognosis of primary FSGS are the initial nephrotic proteinuria and the degree of renal function.

Non-Diabetic Renal Diseases in Diabetic Patients with Emphasis on Infection-Related Glomerulonephritis

ABSTRACT Background: Non -diabetic renal diseases (NDRDs) in diabetics are treatable and therefore have better prognosis. Infection-related glomerulonephritis (IRGN) is being frequently reported as NDRD. Objective: We attempt to study the clinicopathologic spectrum of diabetic patients with biopsy proven IRGN. Materials and Methods: This was a retrospective analysis of renal biopsies performed in diabetic patients from January 2014 to June 2021. Demographic data, clinical features, and other laboratory findings were collected. The renal biopsies were classified into diabetic nephropathy (DN) and NDRD. The patients with diagnosis of IRGN were studied in detail. Results: Of the 1972 renal biopsies done in diabetic patients, 537 were NDRD and 1233 were DN. The commonest NDRD was tubulo-interstitial nephritis (n = 173) followed by IRGN (n = 74). The IRGN cases were in the age range of 5-78 years (median-53.5) with M: F = 3.4:1. The median duration of diabetes was six years, with median HbA1c = 7.5. Proteinuria ranged from 0.041 to 13 g/day (median = 1.95) with median serum creatinine of 3.7 mg%. History of preceding infection was present in nine cases. These patients presented with rapidly progressive renal failure (RPRF, 17), nephritic syndrome (27), nephrotic syndrome (27), and asymptomatic proteinuria (3). Median C3-level was 47 mg/dl. The biopsies showed classic endocapillary hypercellularity with neutrophils in mesangium, 45 cases had associated DN. Immunofluorescence performed in 54 cases showed coarse granular deposits of C3C. Conclusions: IRGN should be kept in mind in diabetic patients presenting with RPRF or nephrotic proteinuria. The biopsy and immunofluorescence helps in accurate diagnosis.

Angiopoietin-like protein 3: a novel potential biomarker for nephrotic syndrome in children.

Angiopoietin-like 3 (ANGPTL3) is a secretory glycoprotein. It has been demonstrated that ANGPTL3 level was upregulated in minimal change nephrotic syndrome (MCNS) kidney tissues. Subsequently, our group found that ANGPTL3 level was closely correlated with nephropathy in vivo and in vitro. Hence, whether ANGPTL3 level could be correlated with the proteinuria level, and assessment of disease severity of nephrotic syndrome (NS) remained to be investigated. This study aimed to analyzed the correlation between the levels of ANGPTL3 in serum and urine of patients with nephrotic syndrome and proteinuria, and assessed the severity of the patients' disease. In future clinical translation, the level of ANGPTL3 in serum, urine will be used as a biomarker to better predict the development of nephrotic syndrome. A total of 200 NS patients and 80 healthy controls (age, 1-18 years) were admitted to our institution between 2021 and 2022. The etiology of NS included primary nephrotic syndrome (PNS, n = 144) and NS with other causes (n = 56). A total of 280 serum samples and 244 urinary samples were collected to determine ANGPTL3 level using enzyme-linked immunosorbent assay (ELISA). Serum ANGPTL3 and urinary ANGPTL3/Cre were remarkably elevated in NS patients compared with those in healthy controls. Furthermore, serum ANGPTL3 and urinary ANGPTL3/Cre were significantly correlated with proteinuria level. Additionally, multivariate linear regression analysis demonstrated that serum ALB was independently correlated with serum ANGPTL3 and PRO/CR was independently correlated with urinary ANGPTL3/Cre in NS patients. Serum ANGPTL3 and urinary ANGPTL3/Cre showed a promising performance in the diagnosis of NS, and served as novel potential noninvasive biomarkers to assess disease severity of NS. Further exploration of the role of ANGPTL3 level may shed a new light on the treatment of NS.

The association of low birthweight and prematurity on outcomes in children and adults with nephrotic syndrome-a NEPTUNE cohort study.

In single-center studies, both preterm birth and low birth weight (LBW) are associated with worse outcomes in childhood nephrotic syndrome. Using the Nephrotic Syndrome Study Network (NEPTUNE) observational cohort, we tested the hypothesis that in patients with nephrotic syndrome, hypertension, proteinuria status, and disease progression would be more prevalent and more severe in subjects with LBW and prematurity singly or in combination (LBW/prematurity). Three hundred fifty-nine adults and children with focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) and available birth history were included. Estimated glomerular filtration rate (eGFR) decline and remission status were primary outcomes, and secondary outcomes were kidney histopathology, kidney gene expression, and urinary biomarkers. Logistic regression was used to identify associations with LBW/prematurity and these outcomes. We did not find an association between LBW/prematurity and remission of proteinuria. However, LBW/prematurity was associated with greater decline in eGFR. This decline in eGFR was partially explained by the association of LBW/prematurity with APOL1 high-risk alleles, but the association remained after adjustment. There were no differences in kidney histopathology or gene expression in the LBW/prematurity group compared to normal birth weight/term birth. LBW and premature babies who develop nephrotic syndrome have a more rapid decline in kidney function. We did not identify clinical or laboratory features that distinguished the groups. Additional studies in larger groups are needed to fully ascertain the effects of (LBW) and prematurity alone or in combination on kidney function in the setting of nephrotic syndrome.

Surufatinib-induced renal thrombotic microangiopathy: first case report and review of literature

Angiogenesis inhibitors such as tyrosine kinase inhibitors (TKIs) are common therapeutics currently used to treat oncologic disease. Surufatinib is a novel, small-molecule multiple receptor TKI approved by the National Medical Products Administration (NMPA) for the treatment of progressive, advanced, and well-differentiated pancreatic and extrapancreatic neuroendocrine tumours (NETs). Thrombotic microangiopathy (TMA) is a well-documented complication of TKIs targeting the VEGF-A/VEGFR2 signalling pathway. Here, we describe a 43-year-old female patient with biopsy-proven TMA and nephrotic syndrome due to surufatinib treatment for adenoid cystic carcinoma. Histological lesions included glomerular endothelial swelling, widening of subendothelial spaces, mesangiolysis, and double contour, which caused nephrotic proteinuria. Effective management was achieved by drug withdrawal and oral anti-hypertensive regents. The management of surufatinib-related nephrotoxicity without compromising its anticancer effects is challenging. Hypertension and proteinuria must be closely monitored during drug use to reduce or stop the dose in a timely manner before severe nephrotoxicity occurs.