Mesangioproliferative Glomerulonephritis Research Articles

TAFRO syndrome associated with C3 nephropathy (an analysis of clinical experience)

Aim. To present a clinical case of TAFRO syndrome – a recently described subtype of idiopathic multicentric Castleman disease of unknown etiology, characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis of the bone marrow and / or renal dysfunction, organomegaly associated with an increase in serum IL-6 secretion.Materials and methods. Herein, we report a young patient diagnosed with TAFRO combined with C3 nephropathy. The patient was treated with glucocorticoids (methylprednisolone), colchicine, sarilumab, rivaroxaban, and symptomatic treatment.Results. Key aspects of diagnosis, treatment and course of the syndrome were discussed. The possibility of the combined course of two rare pathologies – a subtype of idiopathic multicentric Castleman disease and C3 nephropathy is still unclear.Conclusion. The diagnosis of TAFRO syndrome can be considered after the exclusion of a number of infectious, paraneoplastic, systemic connective tissue diseases, POEMS syndrome, liver cirrhosis against the background of autoimmune hepatitis, autoimmune thrombocytopenic purpura, as well as hemolytic-uremic syndrome. Kidney damage in this category of patients, in most of the described clinical cases, is morphologically represented by thrombotic microangiopathy or mesangioproliferative glomerulonephritis. C3 nephropathy in that clinical case seems to be concomitant. Glucocorticoids in high and ultrahigh doses, cyclosporine, IL-6 type inhibitors, as well as anti-CD20 antibodies are used as therapy.

Clinicopathologic Study of Sickle Cell-associated Kidney Disease: A Nigerian Experience.

Improvements in sickle cell disease (SCD) care have resulted in the survival of many patients into adulthood, although this is accompanied by the increased incidence of end-organ damage, including chronic kidney disease (CKD). This study assessed the prevalence, pattern and predictors of renal dysfunction in SCD patients and investigated the associated renal histopathologic changes. We evaluated 105 patients with SCD, for proteinuria, estimated glomerular filtration rate (eGFR), and tubular dysfunction. Renal biopsy was conducted on 22 patients who qualified. Data were analysed using SPSS package version 23. Thirty-seven (35.2%) of the 105 patients had CKD, as defined by an eGFR of 60 ml/min/1.73 m2 and/or proteinuria. The fractional excretion of potassium (FEK) was elevated in all patients, whereas the fractional excretion of sodium (FENa) was elevated in 98.1%. Glomerular filtration rate was negatively correlated with irreversible percentage sickle cell count (r = -0.616, P = 0.0001), FEK (r = -0.448, P = 0.0001) and FENa (r = -0.336, P = 0.004). Age, irreversible percentage sickle cell count, haemoglobin levels and FENa were the major predictors of CKD. The histological pattern in the 22 patients who had biopsies was consistent with mesangioproliferative glomerulonephritis 11 (50%), minimal change disease 6 (27.3%), focal segmental glomerulosclerosis 3 (13.6%) and interstitial nephritis 2 (9.1%). CKD was prevalent in SCD patients, and it was characterised by tubular dysfunction and mesangioproliferative glomerulonephritis. The main predictors of CKD were increased age, severity of vaso-occlusive crisis, worsening anaemia and tubular dysfunction.

Medium-Term Outcome of Cyclosporine in Children with Steroid-Dependent Nephrotic Syndrome: Single Centre experience from Pakistan

Objective: To determine the medium-term outcome of Cyclosporine in children with steroid-dependent nephrotic syndrome from a single centre in Pakistan Study Design: Prospective longitudinal study Place and Duration of Study: Pediatric Nephrology Department of Sindh Institute of Urology and Transplantation, KarachiPakistan from Jan 2014 to Dec 2016. Methodology: All consecutive patients with steroid-dependent nephrotic syndrome of either gender, between 1-12 years of age, were identified and included in this study, who relapsed post-Cyclophosphamide therapy and were prescribed Cyclosporine after renal biopsy. Results: Seventy-five children with steroid-dependent nephrotic syndrome met the inclusion criteria. There were 55(74%) boys with a mean age of 4.3 ± 2.5 years, while the mean age at the start of Cyclosporine therapy was 6.5 ± 1.5 years. All patients were previously treated with Cyclophosphamide, and sustained remission was achieved for 37.6 ± 43.6 weeks. All patients underwent renal biopsy showing minimal change disease in 46(61.3%) subjects, focal segmental glomerulosclerosis in 12(16%), IgM nephropathy in 13(17.3%) and mesangioproliferative glomerulonephritis in 4(5.3%) children. At the last follow-up, 36(48%) patients were in complete remission, 26(35%) achieved partial remission, seven children (9.3%) did not achieve remission at all, 2(2.7%) were lost to follow-up, and 4(5.3%) patients expired. The mean estimated glomerular filtration rate at the start of Cyclosporine was 112.55 ml/min/1.73 m2, which declined to 107.77 ml/min/1.73 m2 at three years. Conclusion: In the medium term, Cyclosporine effectively maintains remission and reduces steroid usage with minimal nephrotoxicity in steroid-dependent nephrotic syndrome.

Presence of Non-Diabetic Kidney Diseases in Biopsy Specimens of Diabetic Patients' Single Center Experience.

The complications of type 2 diabetes mellitus (T2DM) are well known and one of them is diabetic chronic kidney disease (DCKD). Over time, it has become clear that patients with T2DM can have nondiabetic chronic kidney diseases (NDCKD), especially those that affect the glomeruli. Clinical indicators for identifying DCKD from NDCKD with high sensitivity and specificity have not yet been identified. Therefore, kidney biopsy remains the golden standard for DCKD diagnosis in patients with T2DM. Despite some indications for kidney biopsy, criteria for a biopsy differ between countries, regions, and doctors. The aim of the study was to analyze the biopsy findings in our T2DM population and the justification of the biopsy according to widely accepted criteria. This single center retrospective study analyzed data from 74 patients with T2DM who underwent kidney biopsy from January 2014 to January 2021. According to the biopsy data, we categorized31 patients in the DN group, patients with typical diabetic glomerulopathy, 11 patients in the mixed group, patients who had pathohistological elements for both DN and non-DN glomerulopathy, and 32 patients in the non-DN group, patients with primary glomerulopathy not linked with DM. In the non-DN and mixed groups, the most frequent glomerulopathy was mesangioproliferative glomerulonephritis, including IgA and non-IgA forms, found in 10 patients, and membranous nephropathy (MN) in 10 patients. We analyzed several parameters and only the amount of proteinuria was found to be significantly linked to biopsy findings related to DN. With the existing criteria for kidney biopsy, we managed to detect changes in the kidneys in about half of our patients with T2DM. These patients required specific treatment, different from that which we use for DCKD patients.

Sublytic C5b-9 induces TIMP3 expression by glomerular mesangial cells via TRAF6-dependent KLF5 K63-linked ubiquitination in rat Thy-1 nephritis

Rat Thy-1 nephritis (Thy-1N) is an experimental model for studying human mesangioproliferative glomerulonephritis (MsPGN), and its pathological features are glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) accumulation. Although we have confirmed that renal lesions of Thy-1N rats are sublytic C5b-9-dependent, and ECM accumulation is related to tissue inhibitor of matrix metalloproteinase (TIMP) inhibiting matrix metalloproteinase (MMP) activity, whether sublytic C5b-9 can induce TIMP production by GMC in Thy-1N rat and the underlying mechanism remains unclear. In the study, we proved that the expressions of TIMP3, krϋppel-like transcription factor 5 (KLF5) and tumor necrosis factor receptor-associated factor 6 (TRAF6) were simultaneously up-regulated both in the renal tissues of Thy-1N rats (in vivo) and in the GMC exposed to sublytic C5b-9 (in vitro). Further mechanism exploration discovered that KLF5 and TRAF6 as two upstream molecules could induce TIMP3 gene transcription through binding to the same region i.e., −1801nt to −1554nt (GGGGAGGGGC) and −228nt to −46nt (GCCCCGCCCC) of TIMP3 promoter. In the process, TRAF6 mediated KLF5 K63-linked ubiquitination at K99 and K100 enhancing KLF5 nuclear localization and binding to TIMP3 promoter, augmenting its gene activation. Furthermore, the experiments in vivo exhibited that silencing KLF5, TRAF6 or TIMP3 gene could markedly lessen renal KLF5 K63-linked ubiquitination or TIMP3 induction, ECM accumulation and other pathological changes of Thy-1N rats. Besides, the positive expressions of above-mentioned these proteins and ECM accumulation and their correlation in the renal tissues of MsPGN patients were also demonstrated. Overall, our findings implicate that KLF5 and TRAF6 play a promoting role in sublytic C5b-9-triggered TIMP3 gene transcription and expression, which might provide a novel mechanistic insight into rat Thy-1N and human MsPGN.

Oral glucocorticoids with intravenous cyclophosphamide or oral glucocorticoids alone in the treatment of IgA nephropathy present with nephrotic syndrome and mesangioproliferative glomerulonephritis.

Few studies have evaluated the treatment of immunoglobulin A nephropathy (IgAN) patients with nephrotic syndrome (NS) and mesangioproliferative glomerulonephritis (MPGN). The aim of this study was to compare the therapeutic effects of oral glucocorticoids (GCS) combined with intravenous cyclophosphamide (CTX) and oral GCS alone in the treatment of the MPGN-IgAN patients with NS. Biopsy-proven primary IgAN patients who were aged ≥14years at diagnosis, had coexistent NS and MPGN and estimated glomerular filtration rate (eGFR) ≥15mL/min/1.73 m2, and were treated by oral GCS combined with intravenous CTX or oral GCS alone for 6-12months were retrospectively included. The patients in the GCS+CTX (prednisone 0.6-0.8mg/kg/day and intravenous CTX 0.6-1.0g monthly) or GCS (prednisone 0.8-1mg/kg/day) group were rather matched at a 1:1 ratio on key characteristics by propensity score matching. The primary outcome was defined as either complete remission or partial remission at Month 24. The secondary outcome was a composite renal endpoint defined as a 50% decline in eGFR, doubling of serum creatinine or progression to end-stage kidney disease. Among the 146 IgAN patients who met the inclusion criteria, 42 patients were enrolled in the GCS+CTX group, and 42 patients were enrolled in the GCS group after propensity score matching. The clinical and histological parameters were similar between the two groups. Remission occurred more frequently in the GCS+CTX group at Month 6 (88.1% vs 52.4%, P<0.001), Month 12 (88.1% vs 56.1%, P=0.001) and Month 24 (85.0% vs 47.5%, P<0.001) than in the GCS group. Moreover, subgroup analysis revealed that the higher response rate at Month 24 in the GCS+CTX group than in the GCS group was also present in different subgroups defined by sex, age, eGFR or Oxford MEST-C. Notably, we found that eGFR decreased at a lower rate in patients from the GCS+CTX group than in patients from the GCS group [eGFR slope: 0.05(-3.09, 3.67) vs -2.56 (-11.30, 0.86) mL/min/1.73 m2/year, P=0.03]. Based on multivariate Cox regression analysis, GCS+CTX treatment was found to be independently associated with a decrease in risk for the composite endpoint after adjusted by the International Risk Prediction Score with race (hazard ratio=0.17, 95% confidence interval 0.04-0.83, P=.03). There was no significant difference in adverse events (50.0% vs 42.9%, P=0.51) or serious adverse events (7.1%vs 11.9%, P=.71) between the two groups. Oral GCS combined with intravenous CTX is superior to GCS alone in treating MPGN-IgAN patients combined with NS. As the retrospective design and small sample size, our findings need to be validated by a prospective study.

#2776 KIDNEY INVOLVEMENT IN PATIENTS WITH RHEUMATOID ARTHRITIS

Abstract Background and Aims In rheumatoid arthritis (RA) kidney is commonly affected organ with clinical presentation characterized by proteinuria and microalbuminuria, followed by chronic renal failure. RA is associated with reduced kidney function, possibly due to chronic inflammation or the use of nephrotoxic therapies. Renal diseases occurring in patients with RA may have a variable clinicopathological picture. Little is known about the effects of using the novel biological agents on the risk of kidney diseases. The aim of this study was to determine the relationship between effect of therapy and kidney involvement in patients with RA and evaluated the histopathological findings and associated clinical manifestation. Method In this retrospective study 275 patients with diagnosis of RA were included. In 48 patients renal biopsy was performed. The patients were divided in three groups according to changes in management of RA: 1991-2001, 2002-2011 and 2012-2022 year. Data of demographic characteristics, clinical symptoms and pathological diagnosis were extracted from medical records and pathological reports. Results In our study amyloidosis was the most common histologic pattern, followed by chronic glomerulonephritis (GN) and tubulointerstitial nephritis. Renal amyloidosis was diagnosed in 13 patients, membranous GN – in 9, mesangioproliferative GN – in 7 patients, focal segmental necrotizing GN – in 5, focal segmental sclerosis – in 4, minimal change disease – in 3, tubulointerstitial nephritis – in 7 patients. Between 1991 and 2001 year the most common clinical manifestation was nephrotic syndrome and the most common histopathological findings – renal amyloidosis, followed by membranous GN and focal segmental necrotizing GN. The membranous GN was related to the use of gold and its frequency decreased after 2001. The mesangioproliferative GN was the leading cause of kidney disease between 2002–2011 years and focal segmental sclerosis – between 2012–2022. In our study 68 patients had a decrease of glomerular filtration rate (GFR) &amp;lt; 60 mL/min/m2. No kidney biopsies were performed in these cases because no urine abnormalities were detected. We found that age, duration of the disease, arterial hypertension, C-reactive protein were significant risk factors for GFR decline in patients with RA. Patients with RA who are treated with biologic agents are less likely to experience progressive decline in kidney function than those not receiving biologic treatment (hazard ratios {HRs] [95% CI], 0,84 [0,68-1,02]}. Conclusion In all patients with RA, renal function should be monitored and in the case of pathologic results, renal biopsy should be performed. In RA patients with renal disorder, suspected causal drug should be removed from the treatment and specific immunosuppressive therapy initiated. Improved pain management associated with biologic treatment may help to reduce the need for potentially nephrotoxic anti-inflammatory agents such as NSAIDs and certain types of non-biologic DMARDs, which could consequently reduce the risk of drug-induced nephrotoxicity and thereby contribute to the lower risk of renal diseases.

Primary nephrotic syndrome in children in Cape Town, South Africa

Background. Histopathological patterns of childhood primary nephrotic syndrome (PNS) and clinical response to steroids have beenassociated with certain race groups in parts of South Africa. However, there are no recent studies of childhood PNS in Cape Town.Objectives. To describe the demographics, histological subtypes and steroid response of patients with PNS who underwent kidney biopsiesat Red Cross War Memorial Children’s Hospital (RCWMCH) over a 10-year period.Methods. Details of patients with PNS who underwent kidney biopsies in the Paediatric Nephrology Department at RCWMCH between2006 and 2015 were retrospectively recorded.Results. A total of 103 patients were included in the study. Most patients were either of mixed race (42%) or black (36%), with a mean age of6.8 years and a male-to-female ratio of 1.19:1. The most identified histopathological subtype was mesangioproliferative glomerulonephritis(MesPGN; 60% (n/N=62/103)). Of the patients with focal segmental glomerulosclerosis (FSGS), MesPGN and minimal change disease(MCD) 45% (n/N=43/95) were steroid-resistant, and 54% (n/N=51/95) were steroid-sensitive. There was no significant associationbetween any race group and steroid response. Patients with FSGS were more likely to be black, while MCD was more common in mixed-race patients (p=0.04). There was no difference in the likelihood of being mixed race or black between patients with FSGS and MesPGN(p=0.472).Conclusion. MesPGN was the most common histopathological subtype found in our study. There was no significant association betweenrace and steroid response. Patients with FSGS were more likely to be black than mixed race when compared with MCD patients. Race wasnot otherwise significantly associated with any histopathological subtype

Kidney and urinary tract involvement in systemic mastocytosis.

Systemic mastocytosis (SM) is a disorder of excessive mast cell accumulation in tissues due to a somatic gain-of-function mutation, commonly in the KIT gene, which prevents apoptosis of mast cells. Whereas bone marrow, skin, lymph nodes, spleen, and gastrointestinal tract are commonly involved, kidneys are rarely involved directly by SM. However, there are increasing reports of indirect kidney involvement in patients with SM. Novel anti-neoplastic agents to treat advanced forms of SM include non-specific tyrosine kinase inhibitors, which are reported to be associated with kidney dysfunction in some patients. SM is also associated with immune-mediated glomerulonephritis (GN) like mesangioproliferative GN, membranous nephropathy, and diffuse proliferative GN. Kidney injury, in the form of monoclonal deposition disease and primary light chain amyloidosis, is reported in SM associated with plasma cell dyscrasia. In this narrative review, we discuss the various ways kidneys (and the urinary tract) are involved in patients with SM.

The Long-Term Survival Outcome in Older Patients with Different Pathological Types of Chronic Kidney Disease

Introduction: Chronic kidney diseases (CKDs) are prevalent in older people, and renal pathological manifestations are important for diagnosis, treatment, and prognosis. However, the long-term survival outcome and risk factors for older CKD patients with different pathological types are not fully understood and need to be further investigated. Methods: Medical data were recorded and all-cause mortality was followed up in patients who underwent renal biopsy diagnosed in Guangdong Provincial People’s Hospital from 2005 to 2015. Kaplan-Meier analysis was used to identify the incidence of survival outcomes. Multivariate Cox regression models and nomograms were applied to analyze pathological types and other factors for overall survival outcomes. Results: 368 cases were included and the median follow-up was 85 (46.5, 111) months. Overall mortality was 35.6%. The highest mortality was in the mesangioproliferative glomerulonephritis (MPGN) group (88.9%), followed by amyloidosis (AMY) group (84.6%), and the lowest mortality was in the minimal change disease (MCD) group (21.9%). Moreover, multivariate Cox regression model showed that survival times of MPGN {hazard ratio (HR) = 8.215 (95% confidence interval [CI]: 2.735–24.674), p p Conclusion: The long-term survival outcome of older CKD patients showed differences among different pathological types, and MPGN, AMY, age, baseline eGFR, CVA/TIA, and COPD were independent predictors for mortality.

Prevalence and distribution of primary glomerular diseases in Africa: a systematic review and meta-analysis of observational studies.

Glomerulonephritis (GN) is a predominant cause of kidney failure in Africa. The prevalence of primary GNs varies widely across Africa depending on the relative proportion of secondary GNs and genetic predispositions. We assessed the overall and sub-regional prevalence of primary GN and its histologic subtypes in Africa. We searched PubMed, EMBASE and African Journals Online for studies of biopsy-proven primary GNs across all age groups in Africa published between 2010 and 2022. Data for primary GNs [minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), mesangioproliferative GN (MesPGN), membranoproliferative GN (MPGN), post-infectious GN (PIGN), IgA Nephropathy (IgAN), and crescentic GN (CresGN)] were extracted. Pooled prevalence was determined using the random effects model. Seventeen eligible articles (n = 6,494 individuals) from 8 African countries met the inclusion criteria. The overall pooled prevalence of FSGS, MCD, MN, MPGN, MesPGN, PIGN, IgAN and CresGN was 26.10%, 22.40%, 8.40%, 6.40%, 6.40%, 2.60%, 2.60%, 1.40%, respectively. Only 4 studies (23.5%) used light microscopy (LM), immunofluorescence (IF), and electron microscopy (EM) for diagnosis. There were significant differences in the distribution of histologic subtypes in the paediatric compared to the adult population and across geographic sub-regions, with West Africa having a higher prevalence of FSGS. Overall, the dominance of FSGS across most regions and age groups has implications for disease diagnosis and ongoing care. Research efforts to understand the impact of this trend on kidney disease outcomes and efforts to improve kidney biopsy practice as a means of early disease detection are needed in Africa.

Clinicopathological Analysis of Biopsy-Proven Glomerulonephritis in the Pediatric Patients : A Study from Tertiary Care Centre

Objective: To evaluate the clinic-pathological characteristics and their association with biopsy-proven glomerulonephritis in pediatric patients.&#x0D; Study Design: Prospective longitudinal study.&#x0D; Place and Duration of Study: Pediatric Department Nishtar Medical University, Multan Pakistan, from Jan 2014 to Dec 2019.&#x0D; Methodology: During the study, a total of 211 renal biopsy reports of different age groups were studied and analyzed for clinic-pathological features and patterns of direct immunofluorescence.&#x0D; Results: The mean age of 8.6±3.25 years was observed. The most common pathology was focal segmental glomerulo-sclerosis in 86 (40.76) of the patients, followed by mesangio-proliferative glomerulonephritis in 41 (19.43) of the patients. Minimal change disease was seen in 26 (12.32) cases. It was observed that the majority of the patients with diffuse proliferative glomerulonephritis were younger than 11 years old, whereas; 10 (11.2), patients with lupus nephritis, 11 (15.1) and membranous nephropathy, 10 (12.2) were comparatively older.&#x0D; Conclusion: Glomerulonephritis presents a diversified group of diseases with overlapping clinic-pathological features. The present study has reported many significant characteristics which could help diagnose a particular disorder among the pediatric population.

Glomerulopathy in patients with dermatomyositis in early active disease: clinical, pathological and capillaroscopic manifestations, and response to treatment.

IntroductionIdiopathic inflammatory myopathies (IIMs) are a group of systemic connective tissue diseases that present with muscular and extra-muscular manifestations. There are few reports on kidney involvement, especially in dermatomyositis (DM) patients. We evaluated the clinical, laboratory, capillaroscopy, and kidney pathology of patients with DM, who presented with proteinuria during the first year, and followed them for response to treatment.Material and methodsWe evaluated 205 patients with proximal muscle weakness or high muscle enzymes, who referred to the nailfold capillaroscopy clinic from April 2010 to October 2021. Seventy-four patients fulfilled the New 2017 EULAR/ACR Classification Criteria for adult and juvenile IM with probability of ≥ 90% for DM with duration of ≤ 12 months and proteinuria > 350 mg/24 hours. All manifestations of patients with glomerulopathy and their kidney biopsies were reviewed, and they were followed for their treatment response.ResultsFrom 74 patients with DM, 52 female and 22 male, median age 37 (19–65) years, and disease duration of median 4.5 (1–12) months, 2 (2.7%) patients (25- and 28-year-old male) had proteinuria. Their kidney biopsy showed mesangioproliferative glomerulonephritis (GN). There was no case of acute or chronic kidney damage or rhabdomyolysis. Both had high disease activity, high erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), abnormal capillaroscopy, and high anti-Ro positivity with good early response of their kidney function, muscle weakness, and laboratory tests after immunosuppressive treatment for 3–6 months. One patient had capillaroscopy follow-up, and all abnormalities were resolved in 8 fingers. One patient, due to poor follow-up, after 8 months had recurrence of his disease.ConclusionsWe found mesangioproliferative GN as a rare extra-muscular manifestation in patients with DM in the active and early phase of the disease. Full immunosuppressive treatment showed early complete recovery in these patients.

The clinical case: COVID-19 in a child with chronic kidney disease

Since the spread of the novel coronavirus infection, most researchers have noted a low proportion of sick children in general pediatric cohort compared to adults, who had a mild disease course and rare complications. The most frequent clinical manifestations of the disease are respiratory and, some less frequently diarrheal syndromes. The disease has predominantly mild or asymptomatic course. The risk of adverse outcomes in children, similar to adults, clearly correlate with the presence of background chronic pathology. The need for respiratory support prevails in children with a severe premorbid burden. Here, a clinical case of ongoing novel coronavirus infection in adolescent patient comorbid with chronic kidney pathology is described. In adolescence, the patient was diagnosed with mesangioproliferative glomerulonephritis (IgA-nephropathy), and further registered at the dispensary receiving a combination therapy with angiotensin converting enzyme inhibitors and disaggregation drugs. The epidemiological history contained no established contacts with infectious patients. The clinical manifestations of COVID-19 in the patient are represented by catarrhal and diarrheal syndromes, transient renal dysfunction in the acute period of the disease. The onset of coronavirus infection was clinically characterized by symptoms of damaged gastrointestinal tract and was considered as acute gastroenteritis of infectious etiology. Empirically prescribed antibacterial therapy in combination with antiplatelet agents and symptomatic drugs had no effect. The diagnosis of the novel coronavirus infection was verified only on day 4 of hospitalization, clinical and laboratory signs of lung damage emerged. The inflammatory process developed in the patient lungs was secondary to the main pathology. The severity of the patients condition was determined by the presence of respiratory and renal insufficiency. Lung damage with minimal severity complaints and clinical data had a bimodal pattern and required respiratory support. A comprehensive approach to treatment, including respiratory, antiviral, enterosorption, anticoagulation, anti-inflammatory, antihypertensive, hepatoprotective, symptomatic therapy with change in antibacterial drugs allowed to achieve positive dynamics. On day 12 of the illness, the patient required no respiratory support. The presence of symptoms of gastrointestinal tract damage in COVID-19 necessitates the mandatory inclusion of PCR assay for SARS-CoV-2 into diagnostic protocol in patients with diarrheal syndrome to perform etiological disease interpretation.

Kidney damage in HIV infection: pathogenetic aspects, clinical and morphological variants and the role of antiretroviral therapy

The review analyzes the prevalence and pathogenetic aspects of HIV infection. The main clinical and morphological variants of kidney damage in HIV infection are outlined. The prevalence of kidney damage in HIV infection is 20–30%, which are represented by such clinical and morphological variants as HIV-associated nephropathy (VAN), immunocomplex HIV-associated kidney disease, and thrombotic microangiopathy. In patients with HIV infection who are not treated with antiretroviral therapy (ART) the most common type of kidney disease is HIVAT. A decrease in the number of CD4+ cells, high viral load, advanced age, and the presence of kidney pathology in the next of kin are risk factors for the development of HIVAT. Specific risk factors for kidney damage in HIV infection are the use of antiretroviral drugs (tenofovir), the uncontrolled use of which is accompanied by tubular dysfunction. In HIV infection, the degree of immunodeficiency correlates with the severity of kidney damage. The most common histopathological manifestations of kidney damage in individuals with HIV infection are focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, immunoglobulin A nephropathy, and mesangioproliferative glomerulonephritis. Hypertension, nephrotic syndrome, and reduced CD4+ cells are predictive of renal failure in HIV infection. In patients with HIV infection who are treated with ART the appearance of hypokalemia, nocturia, polyuria, microhematuria, and/or subnephrotic proteinuria is indicative of tubulointerstitial disease. To assess the total filtration function of the kidneys in people with HIV infection, the most acceptable formula is CKD-EPI.

MO264: Selective Endothelin a Receptor Antagonist Atrasentan Attenuates Mesangial Cell Injury, Proteinuria and intra-renal proliferative, inflammatory and Fibrotic Transcriptional Networks in a Rat Model of Mesangioproliferative Glomerulonephritis

Abstract BACKGROUND AND AIMS Mesangial cell (MC) activation, characterized by excess proliferation and extra-cellular matrix deposition is the initiating intra-renal event in the pathogenesis of mesangioproliferative glomerulonephritis (MPGN), including IgA nephropathy (IgAN). However, the molecular mechanisms responsible for MC activation and the subsequent podocyte crosstalk resulting in proteinuria have not been well defined. The objective of this study was to determine the role of the endothelin A (ETA) receptor in MC activation, proteinuria and pathogenic intra-renal transcriptional responses in a rat model of MPGN, using atrasentan, a potent and selective ETA antagonist. METHOD MPGN was induced in male Wistar rats by a single IV injection of anti-Thy1.1 antibody (0.5 mg/kg) on day 0. Rats were randomized to receive atrasentan (10 mg/kg, po bid) or vehicle control beginning on Day 1 through Day 7. UPCR was measured on Days 1, 3, 5 and 7; on Day 7, kidneys were fixed, stained and evaluated by light microscopy using a semi-quantitative grading scale by a pathologist, blinded to treatment allocations. RNA-seq was performed on flash-frozen kidney cortex and analyzed using DESeq2 to identify differentially expressed genes followed by gene set enrichment analysis to identify dysregulated transcriptional networks that were cross-validated to the glomerular transcriptome of kidney biopsy samples from IgAN patients (GSE104066). Cell type-specific signatures were derived from a scRNA-seq dataset (GSE171314) from IgAN patients. RESULTS Glomerular injury was characterized histologically by prominent mesangial hypercellularity and matrix expansion, glomerular adhesions, segmental mesangiolysis and glomerulosclerosis, and was significantly attenuated by atrasentan. Tubular injury, including protein casts, tubular degeneration, tubular dilation and interstitial fibrosis, was also observed in the model, although more modest and likely secondary to the glomerular injury, and was also significantly attenuated by atrasentan. The targeted mesangial injury induced by anti-Thy1.1 also resulted in significant proteinuria, which was substantially reduced by atrasentan (Fig. 1). In addition, atrasentan significantly attenuated the increase in kidney weight, likely reflective of the reduced mesangial proliferation, matrix expansion and accompanying inflammation observed histologically. Induction of MPGN in rats was transcriptionally characterized by a downregulation of metabolism gene networks and upregulation of networks associated with proliferation, inflammation and fibrosis, consistent with the hallmark genesets dysregulated in the glomeruli of IgAN patients (Fig. 2). Atrasentan downregulated these intra-renal proliferative, inflammatory and fibrotic transcriptional networks and upregulated metabolism networks (Fig. 2). Analysis using cell-type specific signatures derived from scRNA-seq data from IgAN patients, suggests that atrasentan treatment attenuates anti-Thy1.1-induced gene expression changes in multiple cell types, including mesangial cells, the target cell of injury in MPGN. In addition, although anti-Thy1.1 primarily induces glomerular injury, there was a strong transcriptional signature of failed repair in the proximal tubules, which was attenuated by atrasentan. CONCLUSION This study suggests an important role of the ETA receptor in MC activation, subsequent proteinuria and activation of pathogenic proliferative, inflammatory and fibrotic intra-renal transcriptional networks in MPGN. This further supports the therapeutic potential of atrasentan, a selective ETA receptor antagonist, to attenuate mesangial cell activation, proteinuria and pathogenic intra-renal signaling in MPGNs such as IgAN.

MO261: Sparsentan, The Dual Endothelin Angiotensin Receptor Antagonist (DEARA), Attenuates Albuminuria and Protects from the Development of Renal Injury to a Greater Extent Than Losartan in the GDDY Mouse Model of IGA Nephropathy: A 16-Week Study

Abstract BACKGROUND AND AIMS gddY mice are an IgA nephropathy (IgAN)-prone mouse model that develops albuminuria by 8 weeks (wks) of age with glomerular IgA, IgG and C3 deposits and progressive mesangioproliferative glomerulonephritis. We have previously shown that sparsentan (SP), a novel, highly selective, first-in-class, single-molecule dual endothelin angiotensin receptor antagonist (DEARA) being developed for the treatment of focal segmental glomerulosclerosis and IgAN, protected gddY mice from the development of albuminuria and glomerulosclerosis in an 8-week study. Here we compare the impact of SP and losartan (LS), an angiotensin II subtype 1 receptor antagonist (AT1R), on albuminuria, % of sclerotic glomeruli (GS), podocyte number, and glycocalyx damage in gddY mice treated for 16 weeks. METHOD gddY mice at 4 weeks of age were treated for 8 or 16 weeks either with chow as a control (C) (n = 10) or containing SP at 900 ppm (SP900) (n = 12) or with control chow and LS in drinking water to deliver 30 mg/kg of LS (LS30) (n = 12). Systolic blood pressure (BP) was measured by tail-cuff plethysmography at 8, 12 and 18 weeks of age. Albuminuria/creatinine ratio (ACR) was assessed every 2 weeks until 20 weeks of age. Kidney biopsies (n = 4–5 per group) were taken from a subset of mice sacrificed at age 12 weeks and at the end of the study at 20 weeks of age (5–7 per group) and processed for determination of GS, the number of podocytes assessed by immunohistochemistry using an anti-WT-1 antibody (30 glomeruli per animal), and measurement of the glycocalyx area using FITC-labeled lectin (10 glomeruli per animal). RESULTS gddY mice treated with SP900 or LS30 had an equivalent and significant (P &amp;lt; .01) reduction in BP compared with C mice at 12 and 18 weeks of age (18 weeks of age mean BP ± SD mmHg: C, 147 ± 28; SP900, 100 ± 6; LS30, 101 ± 8). Despite similar systemic hemodynamic effects, SP900 treatment resulted in a greater and more rapid reduction in ACR from baseline compared with either mice treated with C or LS30 during the first 4 weeks of treatment (Fig. 1). Development of GS was significantly attenuated in mice at 20 weeks of age treated with SP900 (P &amp;lt; .001) compared with C mice, but not in those treated with LS30 (mean sclerosis score ± SD: C, 28 ± 17; SP900, 3 ± 1; LS30, 19 ± 21). Compared with C mice at 20 weeks of age, SP900 (P &amp;lt; .0001) and LS30 (P &amp;lt; .05) significantly prevented the reduction in WT-1 immunoreactivity (WT-1 positive cells/glomerulus, mean ± SD: C, 7.3 ± 0.5; SP900, 10.0 ± 0.5; LS30 8.1 ± 0.8). Notably, SP900-treated mice had significantly greater WT-1 staining (P &amp;lt; .0001) and glycocalyx area (Fig. 2) than LS30 mice. CONCLUSION gddY mice treated from 4–20 weeks of age with sparsentan demonstrated a more rapid attenuation of ACR and greater protection from GS than mice treated with losartan. Sparsentan protected the glomeruli from loss of podocytes and glycocalyx to a greater extent than losartan despite equivalent lowering of BP. These results suggest that the ability of sparsentan to protect gddY mice from progression of IgAN nephropathy may go beyond effects mediated through reduction in blood pressure and antagonism of AT1R alone and may be attributed to its dual mechanism of action. If translated to the clinic, these data may support sparsentan as a new approach to the treatment of IgAN.

Sublytic C5b-9 Induces CCL3/4 Production and Macrophage Accumulation in Thy-1N Rats via PKC-α/p65/IRF-8 Axis.

Mesangioproliferative glomerulonephritis (MsPGN) is a common human kidney disease. Rat Thy-1 nephritis (Thy-1N) is an animal model widely used for the study of MsPGN. Thy-1N is not only sublytic C5b-9-dependent, but also related to pro-inflammatory cytokine production and macrophage (Mφ) accumulation in rat renal tissues. In this study, we found that the expression or phosphorylation of chemokine CCL3/4, CD68 (Mφ marker), IRF-8, PKC-α and NF-κB-p65 (p65) were all up-regulated both in the renal tissues of Thy-1N rats (in vivo) and in the glomerular mesangial cells (GMCs) upon sublytic C5b-9 stimulation (in vitro). Further experiments in vitro revealed that the phosphorylated PKC-α (p-PKC-α) could promote p65 phosphorylation, and then p-p65 enhanced IRF-8 expression through binding to IRF-8 promotor (-591 ~ -582 nt and -299 ~ -290 nt). Additionally, up-regulation or silencing of IRF-8 gene promoted or reduced CCL3/4 production, and then regulated Mφ chemotaxis. The underlying mechanism involved in IRF-8 binding to CCL3 promoter (-249 ~ -236 nt), which resulted in CCL3 gene transcription. The experiments in vivo showed that knockdown of renal PKC-α, p65, IRF-8 and CCL3/4 genes could inhibit CCL3/4 production, Mφ accumulation, GMC proliferation and proteinuria of Thy-1N rats. Furthermore, p-PKC-α, p-p65, IRF-8, CCL3/4 expression and Mφ accumulation were also increased in the renal tissues of MsPGN patients. Collectively, these findings indicate that sublytic C5b-9 induces CCL3/4 production and Mφ accumulation via PKC-α/p65/IRF-8 axis, and finally aggravates the pathological changes of MsPGN.

Childhood Steroid-resistant Nephrotic Syndrome: Long-term Outcomes from a Tertiary Care Center.

Introduction:Steroid-resistant nephrotic syndrome (SRNS) is a rare condition that accounts for about 10% to 20% of all nephrotic syndromes in children. While calcineurin inhibitors induce remission in the majority, the data on long-term outcomes are limited. This retrospective study aimed to look at the clinical profile, biopsy findings, and long-term treatment outcomes in children with SRNS.Methods:The records of all children (1–18 years) with SRNS with biopsy findings of minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or mesangioproliferative glomerulonephritis, who received treatment for a minimum period of 12 months and were in follow-up during the years 2007–2018 at a tertiary care teaching hospital were retrieved. The clinical, histopathological, and biochemical factors and treatment outcomes were recorded and analyzed.Results:Ninety-one (72 boys) children with a median (interquartile range [IQR]) age of onset of nephrotic syndrome as 48 (24–87) months were included. MCD and FSGS were the most common histopathological types (57.1% and 36.3%, respectively) and 62 (68.1%) patients had late steroid resistance. Calcineurin inhibitors (CNIs) were used in 86.8% of the children, and response rates with cyclosporine and tacrolimus for complete remission (CR) were 80% and 73.7%, respectively, with median (IQR) time to response being 3 (2–4) months. The presence of MCD on histology and the use of CNIs were significantly associated with CR (P < 0.01). At a median (IQR) follow-up of 5 (3–7) years, 76 (83.5%) children had either CR or partial remission, four (4.4%) developed chronic kidney disease and five (5.5%) died (three due to end-stage renal disease and two of infective complications).Conclusion:SRNS children with MCD on biopsy, late resistance, and response to CNIs have better long-term outcomes. Most patients respond to CNIs within the first 6 months of use and need therapy for at least 24 to 36 months.

Therapeutic Response and Long-Term Renal Outcomes in Childhood Idiopathic Steroid-Resistant Nephrotic Syndrome: A Single-Center Study

Purpose: We aimed to evaluate therapeutic response and long-term renal outcomes of childhood idiopathic steroid-resistant nephrotic syndrome (iSRNS). Methods: We retrospectively reviewed treatment regimens, especially calcineurin inhibitor (CNI), pathologic diagnoses, and long-term renal outcomes of iSRNS patients for 30 years. Results: Of 516 patients with idiopathic NS, 52 (10.1%) had iSRNS. Renal biopsies from 48 patients showed minimal change disease (MCD) in 23 (47.9%), focal segmental glomerulosclerosis in 24 (50.0%), and mesangioproliferative glomerulonephritis in 1 (2.1%). The median follow-up period was 66.5 (range, 4–275) months, and 90.4% of them were treated with a CNI. CNI induced remission in 70.2% within 50.4 ± 43.5 days. Of the patients with MCD and focal segmental glomerular sclerosis (FSGS), 86.4% (19/22) and 45.0% (9/20) (p = 0.005) responded to CNI, respectively. Mean time until remission after using CNI was longer with FSGS (90.4 ± 54.0 days) than with MCD (29.6 ± 26.3 days) (p = 0.010). CNI-responsive patients with FSGS or MCD showed preserved renal function, and CNI nonresponsive MCD patients also showed preserved renal function during follow-up. However, end-stage renal disease (ESRD) progressed in 8 out of 11 patients with FSGS nonresponsive to the CNI for an average of 44.9 ± 18.4 months after diagnosis. Conclusion: Different response rates and times for remission were achieved with the CNI according to the pathology of iSRNS. All MCD patients regardless of CNI response and all CNI-responsive patients with FSGS showed excellent renal outcomes, while almost all FSGS patients nonresponsive to CNI eventually progressed to ESRD.