Membranous Proliferative Glomerulonephritis Research Articles

IgM kappa proliferative glomerulonephritis with monoclonal immunoglobulin deposition complicated with nocardiosis dermatitis: a case report and review of literature

RationaleMonoclonal gammopathy of renal significance (MGRS) represents a group of disorders caused by monoclonal immunoglobulin (M protein) secreted by B cells or plasma cells. Proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMID) is a glomerular disease and a form of MGRS. Here, we presented a rare case of a patient with IgM kappa PGNMID complicated with nocardiosis dermatitis.Patient concerns and diagnosesA 56-year-old man was admitted to the hospital because of cutaneous purpura and proteinuria. His initial pathological diagnosis indicated membranous proliferative glomerulonephritis, IgM(++), and subacute interstitial nephritis. Based on further examination, he was finally diagnosed to have IgM kappa PGNMID and subacute interstitial nephritis. After the initial diagnosis, the patient received hormonal therapy. During the treatment, nocardiosis dermatitis emerged as a complication, and the hormonal therapy was gradually reduced. The patient refused further treatment with rituximab, and his health is currently stable.OutcomesIgM kappa PGNMID complicated with nocardiosis dermatitis is an extremely rare occurrence. Laboratory examination and pathological analysis are required to confirm the diagnosis of this disorder. Timely and accurate diagnosis is essential for the appropriate treatment of PGNMID.

Prevalence of MGCS Among Patients With Monoclonal Gammopathies.

Monoclonal gammopathies is a common condition especially among elderly people,1 most commonly a “monoclonal gammopathy of undetermined significance” (MGUS), which usually remain asymptomatic, without characteristics of active malignancy.2 In some cases, monoclonal gammopathies are associated with a variety of syndromes that may involve the kidneys (characterized as monoclonal gammopathy of renal significance [MGRS]),3 peripheral nerve, skin, or less commonly organs such as the eyes, the muscles, or may even cause nonorgan-confined systemic syndromes. These syndromes have been termed as “monoclonal gammopathy of clinical significance” (MGCS),4 which usually are associated with a nonmalignant B-cell or plasma cell clones and do not fulfill the typical criteria of symptomatic multiple myeloma (MM) or Waldenström’s macroglobulinemia (WM).5 The manifestations of MGCS result from various properties of the monoclonal protein (deposition, autoantibody activity, or other mechanisms) or of the clone (such as ectopic production of cytokines), while in some syndromes the pathophysiological mechanisms remain unknown. Their diagnosis is challenging, requiring a high degree of suspicion or target organ biopsies. Because of the difficulties in their recognition, their true prevalence among patients with monoclonal gammopathies is unknown. On the contrary, a recent prospective study in Iceland reported a prevalence of monoclonal gammopathies of almost 5% among subjects aged >40 years.6 Thus, the prevalence of MGCS may be significantly underestimated due to the heterogeneous phenotype, the difficulties in establishing the diagnosis, and the low degree of suspicion. To provide an estimate of the prevalence of MGCS among patients with monoclonal gammopathies, we analyzed the database of a referral center (Plasma Cell Dyscrasia Unit, Department of Clinical Therapeutics, Athens, Greece). This prospectively maintained database includes all patients with monoclonal gammopathies who are referred for evaluation or treatment. The analysis included all patients with monoclonal gammopathy with or without any concomitant symptoms or any laboratory abnormalities. Because of an increasing interest in MGCS after 2010, and subsequent rising awareness and diagnostic sensitivity, we excluded earlier referrals and focused only on 3138 consecutive patients who were referred and diagnosed with a monoclonal gammopathy between January 1, 2010 and December 31, 2021. The final diagnosis was a MGCS-related syndrome in 135 patients (4.3%) and was MGUS or smoldering myeloma (SMM) or asymptomatic WM (aWM) in 1437 patients (46%), symptomatic MM in 1145 patients (36%), symptomatic WM in 108 patients (3%), and immunoglobulin light chain (AL) amyloidosis in 320 patients (10%). In particular, the proportion of MGCS among those with <10% clonal cells was 5.8%, and among those with >10% clonal cells was 3.8%. Among those with MGCS, the majority was diagnosed either with MGRS (n=51) or an IgM-related neuropathy (n=58). Other specific MGCS diagnoses included POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes) syndrome (n=13), Schnitzler’s syndrome (n=3), necrobiotic xanthogranuloma (n=3), or scleromyxedema (n=2), and other rare syndromes such as TEMPI (Telangiectasias, Elevated erythropoietin and erythrocytosis, Monoclonal gammopathy, Perinephric fluid collections, Intrapulmonary shunting) syndrome (n=2), IgM retinopathy (n=1), Clarkson’s syndrome (n=1), and crystalglobulinemia (n=1). Among patients with MGRS, the majority (n=43) had monoclonal immunoglοbulin deposition disease (MIDD) (light chain deposition disease [LCDD]:31, heavy chain deposition disease [HCDD]:2, H/LCDD:10), 4 patients had C3 nephropathy, 2 patients had fibrillary glomerulonephritis, 1 patient had membranous proliferative glomerulonephritis (MPGN), and 1 patient had immunotactoid glomerulonephritis (GN). Peripheral neuropathy with a concomitant monoclonal gammopathy was the most common coexisting condition among non-AL amyloidosis patients, with 73% having IgM and 37% a non-IgM paraproteinemia. A causal relationship between monoclonal gammopathy and neuropathy was established for 42% of those with non-IgM neuropathy and these patients mainly had POEMS syndrome. The median age of the MGCS patients was 64 years, not significantly different in clinical terms from that of patients with SMM/MGUS, AL amyloidosis, symptomatic MM, and symptomatic WM, which was 65, 65, 67 and 70 years, respectively (Table 1). The baseline level of monoclonal immunoglobulin among MGCS patients was low (median, 0.4 g/dL) and significantly lower than in patients with MGUS/SMM/aWM (median, 1.04 g/dL). The median bone marrow (BM) infiltration by clonal cells in patients with MGCS was 10%, and was 7% in the MGUS/SMM group, 15% in patients with AL amyloidosis, 50% in patients with symptomatic MM, and 40% for patients with symptomatic WM. Among patients with MGCS, 56% had kappa light chain and 42% had lambda light chain, while 2% were biclonal (shown in more details in Table 1). Among patients with MGCS, there were very few who progressed to symptomatic myeloma (1 with MIDD and 1 with Clarkson, none of which fulfilled myeloma criteria at the time of diagnosis) and 1 patient to symptomatic WM with anemia and high bone marrow infiltration. Although there were several patients with bone marrow infiltration >10%, none of them progressed to fully blown myeloma with hypercalcemia, renal insufficiency, anemia, bone lesions (CRAB) criteria. Most patients with MGCS received anticlonal therapy, mostly bortezomib-based regimens, immunomodulators (IMiDs), and anti-CD38 monoclonal antibody, in the more recent periods. In patients with B-cell clones, therapy was anti-CD20 based (rituximab). Nonclone targeting therapies were used in patients with specific syndromes such as Schnitzler’s syndrome (pefloxacin and anakinra) and Clarkson’s disease (immunoglobulin). A significant proportion of patients with IgM-related neuropathy received only supportive therapy. Table 1 - Baseline Characteristics of Patients Included in the Analysis N Median Age, y M-peak Baseline, g/dL Median BM Infiltration (%) IgA (%) IgG (%) IgM (%) Kappa (%) Lambda (%) MGCS 135 64 0.4 10 9 36 19.5 51.5 24 MGRS 51 54 0.2 15 12 41 2% 66 33 POEMS 13 58 0 3 23 77 0 8 92 IgM neuropathy 58 66.5 0,57 0 0 0 100 90 10 Necrobiotic xanthogranuloma 3 71 1.5 12 0 100 0 50 50 Schnitzler 3 47 0.5 0 0 0 100 100 0 Scleromyxedema 2 0.4 5 0 100 0 50 50 TEMPI 2 2.2 30 0 100 0 100 0 Clarkson 1 2.2 30 0 100 0 100 0 IgM retinopathy 1 0.9 8 0 0 100 100 0 Cryocrystalglobulinemia 1 46 0.95 8 0 100 0 100 0 MGUS/SMM/aWM 1437 65 1.04 7 21 68 11 65 35 MGUS 927 70 0.6 5 15 57 24 62 38 SMM 474 65 1.4 15 26 69 0 66 34 aWM 36 69 1.02 20 0 0 100 73 27 AL 320 65 <0.2 15 13 35 2 23 67 MM 1145 67 2.88 50 24 56 0.2 69 31 WM 108 70 2.3 40 0 0 100 77 23 AL = immunoglobulin light chain amyloidosis; aWM = asymptomatic Waldenstrom Macroglobulinemia; BM = bone marrow; MGCS = monoclonal gammopathy of clinical significance; MGRS = monoclonal gammopathy of renal significance; MGUS = monoclonal gammopathy of undetermined significance; MM = multiple myeloma; M-protein, skin changes; POEMS = polyneuropathy, organomegaly, endocrinopathy; SMM = smoldering myeloma; TEMPI = telangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, intrapulmonary shunting; WM = Waldenström’s macroglobulinemia. To the best of our knowledge, this is the first study attempting to evaluate the prevalence of MGCS among patients with monoclonal gammopathies and found that among our patients it was almost 4%. In our study, the most common diagnoses were MGRS and IgM-related neuropathy; AL amyloidosis, although considered in the spectrum of MGRS and MGCS,7 is associated with a more aggressive clinical presentation and dismal prognosis requiring immediate treatment, being a unique entity. However, given the prevalence of monoclonal gammopathy in the general population and the heterogeneous clinical presentation of these syndromes, there is probably a significant number of patients with MGCS who remain undiagnosed. These observations are of clinical relevance because patients with MGCS, unlike patients with MGUS, require treatment and may suffer from complications associated with an otherwise nonmalignant condition. Nonetheless, the establishment of MGCS diagnosis requires a high degree of clinical suspicion due to their rarity and highly heterogeneous clinical presentation. Importantly, the demographic and clonal characteristics of most patients with MGCS do not differ from other symptomatic or asymptomatic monoclonal gammopathies making the diagnosis even more challenging, although some specific patterns may exist (eg, POEMS was almost always associated with lambda light chain8 [except in 1 case], while LCDD was more often associated with kappa light chain isotype9). Patients often experience unexplained and apparently unrelated symptoms and the collaboration of different specialties such as hematologists, nephrologists, dermatologists, cardiologists, neurologists is crucial; often the diagnosis may require biopsy of the target organ, especially when kidneys and skin are involved10,11 and an experienced pathologist plays a key role in the diagnosis of these disorders. The causal link of a monoclonal gammopathy with a syndrome is often difficult to prove; on the contrary, new entities may be included among the MGCS spectrum in the future. This has an impact on treatment decisions, as in most cases these diseases are not life-threatening but unnecessary chemotherapy should also be avoided. Therapy of MGCS is based on the use of anticlonal regimens and depends on the origin of the clone (plasma cell, lymphocyte, or lymphoplasmacytic clones),12 similar to that used for AL amyloidosis, most often based on the bortezomib combinations or IMiD-based when neuropathy (as in POEMS) predominates, while the availability of anti-CD38 monoclonal antibodies expands treatment options.13,14 However, in some of these syndromes, management may be based on the nonclonal targeting therapies, or just on supportive therapy or immunosuppressive agents.15–17 The major limitation of our study is that it included patients from a referral center, which is probably associated with a selection bias; however, it is unlikely that the true prevalence of these syndromes can be evaluated in the general population. Thus, our estimations reflect our center’s MGCS frequency rather than the real incidence of MGCS in the population, which remain to be fully described. An approach could be to evaluate their prevalence within the context of a screening program, but this would require a more intensive use of diagnostic tools. Our results should be further validated in other referral centers and ideally within well-designed collaborative studies in order to improve the diagnosis and management of patients with MGCS. It is also important that physicians across different disciplines be informed and educated about these conditions so that patients be appropriately referred and diagnosed and treated timely and accordingly. AUTHOR CONTRIBUTIONS FT analyzed and collected data, performed statistical analysis, and wrote the article. DF, MG, IN-S, VS, PM, MM, EE-P, NK, ET, and MAD analyzed and collected data and critically reviewed the article. EK designed the study, analyzed and collected data, performed statistical analysis, and wrote the article. DISCLOSURES EK has received honoraria from Amgen, Janssen, Genesis Pharma, Takeda, and Prothena. MAD has received honoraria from Amgen, Celgene, Janssen, and Takeda. ET has received honoraria from Medtronic, Celgene, Janssen, and Amgen, and is an editor for HemaSphere. MG has received honoraria from Takeda, Amgen, and Novartis. All the other authors have no conflicts of interest to disclose. SOURCES OF FUNDING The authors declare no sources of funding for this manuscript.

PS-R05-3: SEVERE GLOMERULAR MICROANGIOPATHY IN A PATIENT WITH NEPHROTIC SYNDROME FOLLOWING TAKAYASU ARTERITIS

Introduction: Takayasu arteritis (TA) is a large vessel inflammation that predominantly involves aorta and its main arteries. TA-caused kidney injury is known to be mainly due to renal artery stenosis. However, glomerulonephritis including membranous proliferative glomerulonephritis, focal segmental sclerosis, or crescentic nephritis has been histologically identified in some TA cases. Case description: A 69-year-old female presented with leg edema and refractory hypertension with nephrotic range proteinuria (17.0 g/gCr). She exhibited &gt; 10 mmHg blood pressure discrepancy between left and right upper limbs and severe aortic regurgitation. Lab test showed high level of C-reactive protein and high erythrocyte sedimentation rate. Contrast-enhanced computed tomography identified wall thickening of the left subclavian artery, which led to the diagnosis of TA. Renal biopsy demonstrated that double basement membrane, enlarged subendothelial space, and mesangiolysis with no immunoglobulin deposition. Although azilsartan 40 mg QD and nifedipine 30 mg BID had been prescribed, systolic blood pressure (sBP) was still &gt; 160 mmHg. Thus, while oral prednisolone was started to suppress TA-induced inflammation, azilsartan was replaced with sacubitril valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), for treating refractory hypertension. After a few weeks, sBP was decreased to 130 mmHg with sacubitril valsartan 200 mg QD and proteinuria was dramatically improved to 0.5 g/gCr. Discussion: TA commonly involves the renal artery, leading to stenosis and subsequent ischemic nephropathy. However, no stenosis and occlusion were observed in renal artery of this case. In addition, small vessel inflammation in the kidney such as vessel wall necrosis and immune cells infiltration around arterioles was not found. Serum levels of pro-inflammatory cytokines including vascular endothelial growth factor and interleukin-6, a well-known contributors for progression of TA-related inflammation, were within the normal range. The results indicate that TA-caused hypertension, but not vessel inflammation induced by TA, seems to play a pathological role for development of glomerular microangiopathy in this case. A previous study showed that 70% of TA patients presenting with glomerular lesion has severe hypertension and intimal thickening in renal arterioles was observed more frequently in TA patients presenting with glomerular lesion when compared to those without glomerulonephritis, which supports our hypothesis. In the present case, ARNI significantly reduced sBP which might directly contribute to the improvement of proteinuria. ARNI can be potent to control hypertension more effectively than conventional hypertensive agents in TA patients.

Daily Hemodialysis Helps Critical Nephritic Lupus Patient: A Case Report

Background: Nephritic lupus is the most common and serious complication of systemic lupus erythematosus (SLE) and is associated with a worse prognosis. Hemodialysis is effective in alleviating symptoms and renal involvement in a nephritic lupus patient.&#x0D; Method: A 33-year-old female was diagnosed with SLE in September 2017. She was also diagnosed with diffuse membranous proliferative glomerulonephritis, as confirmed with a kidney biopsy. She complained of gradual onset limb weakness and peripheral edema 3 months before admission. She was treated with 6 cycles of cyclophosphamide and continued with methylprednisolone 16 mg once daily, hydroxychloroquine 200 mg once daily, and myfortic 360 mg twice daily. A day before ICU admission, her creatinine level was increased to 4.6 mg/dl with an estimated GFR of 12 ml/min and her symptoms then worsened into seizures and lung edema. Daily hemodialysis with heparin-free SLEDD was performed. About 2L was extracted for the first 6 hours with Qb 150 ml and Qd 300 ml and was continued until the day after. For the next 4 days, 3L was extracted per day with Qb 200ml and Qd 500 ml. The patients’ hemodynamic status was within normal limits during dialysis period. The condition improved and the patient was transferred to the ward.&#x0D; Discussions: Hemodialysis is a way to solve kidney problems in in nephritic lupus and SLE patients in general. It should not only be employed for mainly kidney problems but could be beneficial in autoimmune patients with conditions such as nephritic lupus. Slowly extracted dialysis type would be a good and inexpensive option to resolve nephritic lupus in compromising lupus patients. Filtration is ensured and solute removal is achieved relatively equivalent to CRRT.&#x0D; Conclusion: Daily hemodialysis could increase renal salvation by providing less creatinine serum and removing accumulated fluids. The SLEDD type could be used for critical nephritic lupus patients with reduced hemodynamic perturbations, minimal anticoagulant, and lower cost.

Serum and urine ANGPTL8 expression levels are associated with hyperlipidemia and proteinuria in primary nephrotic syndrome

BackgroundThis study aimed to investigate the expression characteristics of ANGPTL8 in patients with primary nephrotic syndrome and its possible correlation with hyperlipidemia and proteinuria.MethodsANGPTL8 levels were determined using an enzyme-linked immunosorbent assay in 133 subjects with PNS and 60 healthy controls.ResultsCompared with healthy controls, subjects with primary nephrotic syndrome had higher levels of serum and urine ANGPTL8 (P < 0.001). In primary nephrotic syndrome patients, serum ANGPTL8 was positively correlated with cholesterol (r = 0.209, P < 0.05) and triglycerides (r = 0.412, P < 0.001), while there was no correlation with 24 hUTP. Urine ANGPTL8 was positively correlated with high-density lipoprotein cholesterol (r = 0.181, P < 0.05) and was significantly negatively correlated with creatinine (r = − 0.323, P < 0.001), eGFR (r = − 0, P < 0.001) and 24 hUTP (r = − 0.268, P = 0.002). Interestingly, the urine ANGPTL8 concentrations in membranous nephropathy and mesangial proliferative glomerulonephritis pathological types were different.ConclusionsSerum and urine ANGPTL8 levels in primary nephrotic syndrome patients were correlated with blood lipid levels and proteinuria, respectively, suggesting that ANGPTL8 may play a role in the development of primary nephrotic syndrome hyperlipidemia and proteinuria.

POS-064 HEPATITIS C3 GLOMERULOPATHIES: CASE PRESENTATION OF TH THERAPEUTIC CARE

Isolated C3 glomerulonephritis (CNG3) are rare glomerulopathies defined by the presence of glomerular deposits visible in OM and containing C3 complement deposits, without immunoglobulin IF deposits. These deposits are usually secondary to an impairment of the alternative complement pathway. We report the case of an infection with hepatitis B virus associated with membranous proliferative glomerulonephritis with C3 deposits. It's a rare entity that poses a real problem since there is no well-established consensus faced to th therapeutic emergency. CASE DESCREPTIVE PRESENTATION We present the case of 52 years old aged man, hypertensive and followed for chronic renal failure for 4 years, poorly observing therapeutic, his causal nephropathy was not yet identified. He was referred by his GP for rapid worsening of his renal function with creatinine numbers ranging from 172 micro moles in May to 342 in early August to 476 at the end of August and 625 in early September 2019 with high blood pressure figures. Two-cross proteinuria and hematuria with proteinuria at 3 grams / 24 hours were noticed. Faced with this rapid worsening of renal function, the patient received a renal biopsy puncture that showed a membrano-proliferative glomerulonephritis with isolated c3 depositis. An etiological assessment was carried out with a viral serology which was in favor of active hepatitis B with positive HBs antigen with 3150 viral load. The C hepatitis and HIV serologies were negative. In addition, the C3 complement fraction was consumed and anti-DNA, anti-nuclear, anti-neutrophil cytoplasmic were negative. It was probably a membranous proliferative glomerulonephritis with C3 deposits secondary to infection with the B hepatitis virus. The patient was initially treated with Entecavir, then with corticosteroid therapy containing solumedrol bolis 500 mg for three days followed by full dose steroids. The evolution was marked by a dependence on dialysis, then, after a short delay in starting intensive coticotherapy, the patient developped a fulminant B hepatitis with a pleuro-pericarditis which led to the death of the patient. This is a rare association of HBV infection and GNC3 that has not well responded to treatment. The search for renal HBV DNA is ongoing. The response to treatment had not been observed because of the appearance of fatal secondary complications of high dose of corticosteroid therapy.The dilemma is to find the best approach to treat and save these patients witch vital and a renal prognosis are threatened

Immunoglobulin G4-Related Kidney Disease with Membranous Proliferative Glomerulonephritis Presenting with a Renal Pelvic Mass

Immunoglobulin G4 (IgG4)-related kidney disease is a chronic immune-mediated fibro-inflammatory disorder characterized by multiple organ infiltration with IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis or tumefactive lesions. Previous studies have explored IgG4-related kidney disease, increasing our understanding of its clinical manifestations, and pathological and radiologic findings. However, IgG4-related kidney disease can be misdiagnosed since it mimics malignancies. We report a case of a 77-year-old Korean man diagnosed with IgG4-related kidney disease with membranous proliferative glomerulonephritis, presenting with a renal pelvic mass suspected of being malignant.

P0510INFLAMMATORY BOWEL DISEASE IN KIDNEY TRANSPLANTATION:CASE REPORT

Abstract Introduction Kidney transplantation has become the treatment of choice for chronic end-stage renal disease because it improves not only the quality of life of patients but also their survival rate. However, several complications can be observed in transplant patients such as immune rejection, infections and recurrence of initial nephropathy etc. Case summary A 21-year-old man diagnosed with chronic end-stage renal failure 5 years ago with a renal biopsy showing an aspect of proliferative glomerulonephritis. The study of the alternate complementary path show a C3 low level, C4 and CH50 normal level, H factor and I factor was normal too. The patient presented purpuric skin lesions with a biopsy of granular deposits of C3. We started extra renal purification by peritoneal dialysis and the patient had, one year later, a kidney transplant from his mother. Ten month later, we have notice a progressive renal function decline with an aspect of proliferative membranous glomerulonephritis with deposits predominant of c3 in graft biopsy. The diagnosis of the recurrence of the initial nephropathy was made but the treatment was delayed by the onset of cutaneous leishmaniosis. Few months later the patient was presented with diarrhea lasting more than a month, which led us to do a colonoscopy, which objectified an aspect of chronic inflammatory bowel disease evoking earlier a Crohn's disease. Therefore, we stopped tacrolimus and put the patient on full dose corticosteroid therapy and azathioprine without having a remission, and appearance of skin lesions at the elbow and pelvis evoking pyoderma gangrenosum in skin biopsy. In addition, the patient has presented an ischemic retinal damage probably related to a deregulation of the alternate complement pathway. Discussion The complement system is not only a host defense system against microbes, but also a surveillance system that contributes to maintain tissue homeostasis and tissue repair. However, uncontrolled complement activation can induce tissue damage, and inappropriate activation is involved in the pathogenesis of various conditions like autoimmune diseases, sepsis and transplant and extensive inflammation and tissue damage. The impairment of alternative path can explain the extra-renal manifestation of this patient especially the appearance of inflammatory bowel disease witch can be explained by impaired local immune defense in the gut. Conclusion Immune system abnormalities can occur after kidney transplantation this leads to the appearance of several inflammatory abnormalities such as chronic inflammatory bowel disease which may in our case be due to an abnormality of the alternate pathway of the complement.

P0082CHARACTERISTICS OF ADULT PATIENTS WITH ATYPICAL HEMOLYTIC UREMIC SYNDROME IN RUSSIA

Abstract Background and Aims Atypical hemolytic uremic syndrome (aHUS) is complement mediated thrombotic microangiopathy (TMA), caused by genetic abnormalities in the complement gene cluster. Information about the course of aHUS in the adult population in Russia is not enough accumulated. This study presents the characteristics of Russian adult patients (pts) with aHUS. Aim To assess the characteristics of adult pts with aHUS in Russia. Method statistical analysis of retrospective and prospective data The study included 243 pts with acute TMA (microangiopathic hemolytic anemia, thrombocytopenia, decreased haptoglobin and / or blood schizocytosis, kidney damage) from different regions of Russia. All patients were tested for ADAMTS-13 activity, and there were no accidents of TTP in our study. Cases of acute TMA associated with pregnancy and childbirth (n=134), systemic diseases (n=10), anticancer drugs treatment (n=1) and sepsis (n=13) were excluded. 85 pts with diagnosis of aHUS were selected for further analysis. Results Characteristics of pts are presented in table 1. The average age at the time of acute episode was 32.4 years, the disease was equally common among men and women. Relapsing course was rare (n=11, 13%), the maximum number of relapses – 5. In the debut, 67.8% of pts had signs of kidney damage, in 21% - gastrointestinal tract, 4.8% - CNS, 4.8% - pulmonary thromboembolism, 1.6% - visual impairment. During the acute episode, extrarenal manifestations were detected in 70% of pts, while in 38 cases (44.7%), multiple organ failure (MOF) developed with simultaneous damage from 3 to 7 organs. The most commonly observed symptoms of gastrointestinal lesions (n = 39, 45%), CNS (n = 32, 37%), heart (n = 18, 21%), less often - the organ of vision (n = 10, 12%). Kidney damage was characterized by the development of AKI in 70%, in the rest - urinary syndrome, arterial hypertension, the initial signs of renal dysfunction in various combinations. A morphological examination of kidney was performed in 40 pts (kidney biopsy - 35, autopsy - 5): acute TMA was detected in 28 pts (70%), chronic TMA - in 7 (17.5%), a combination of acute and chronic TMA - in 2 (5%), a combination of IgA-nephropathy and TMA - in 1 case (2.5%) and in 2 patients a membrane-proliferative glomerulonephritis pattern with TMA. Genetic analysis was performed in 19 pts (22%), in 7 of which (37%) identified gene variants associated with the development of aHUS (C3 in 3 pts, CFHR5 in 2 pts, CFH in 2, in 1 case - MCP and in 1-DGKE). In addition, variants of genes of the complement system with an unclear clinical value were found in all pts (n = 19). 72% of pts (n = 61) needed renal replacement therapy, almost all pts received plasma therapy (83%) and anticoagulants (85%). Only 13 pts (15%) received complement-blocking therapy with eculizumab. In the outcome of the acute episode in 12 cases (14%) renal function fully recovered, in 20 pts (23%) signs of renal dysfunction persisted (CKD 2–4 stages), 53 pts (62.3%) reached ESRD, 10 pts died (12%). Conclusion The features of aHUS in our cohort were: 1. Severe course with the development of MOF in 45% of cases 2. High frequency of ESRD in the outcome of aHUS (62.3%) 3. The incidence of genetic mutations (37%) is comparable to foreign cohorts

Impact of IgG Fc-fragments on experimental glomerulonephritis induced by &lt;i&gt;Streptococcus pyogenes&lt;/i&gt; strain binding various immunoglobulin classes

The pathogenesis of poststreptococcal glomerulonephritis (PSGN), a major complication of acute infections caused by group A streptococci (GAS) remains unclear. Several theories, based on the role of certain streptococcal virulence factors, as well as immunological mimicry between GAS and renal tissue, have been proposed. Earlier, we reported that many virulent clinical GAS isolates showing confirmed nephritogenic activity were capable of nonimmune Fc binding of monomeric or aggregated IgG. Moreover, a rabbit model of PSGN allowed to obtain findings regarding a crucial role of streptococcal IgG Fc binding proteins belonging to the M family surface proteins, in the onset of PSGN. Rabbits injected with inactivated IgGFcBP-positive streptococci, acquired changes in the renal tissue with deposited IgG and complement C3, as well as signs of immune inflammation characteristic for human PSGN. Also, it was shown that the induction of experimental glomerulonephritis could be inhibited after normal IgG or its purified Fc fragments were inoculated at early stages of the process. The data obtained in rabbits injected with group A streptococcal type M60 also showed pathogenic functions of the IgA Fc-binding proteins of GAS. The aim of the study was to examine inhibiting activity of the purified rabbit IgG Fc fragments on the manifestations of glomerulonephritis induced by S. pyogenes strains capable of binding diverse forms of immunoglobulins such native IgG, immune complexes, and IgA.Materials and methods. GAS strains of emml, emml2 and emm60 genotypes were used to induce PSGN or IgA-nephropa-thy in rabbits. Fc fragments derived from rabbit IgG were obtained by enzymatic digestion and purified by affinity chromatography on a protein G-sepharose FF column. Immunomorphological changes of renal tissue were estimated by morphometric analysis.Results. In the present study, using the rabbit model, we revealed pathological changes of different intensity and localization in the renal tissue. For streptococci of the emm1 and emm12 genotypes, PSGN was characterized by deposition of IgG or IgG-anti-IgG immune complexes within the basal glomerular membrane. Morphological changes were evaluated as a membranous-proliferative glomerulonephritis. Meanwhile, IgA-glomerulonephritis is characterized by deposition of IgA in mesangial cells of glomeruli, leading to the mesangial-proliferative glomerulonephritis or IgA-nephropathy. Intravenously administered purified Fc fragments derived from normal rabbit IgG varied in effects on pathological processes: (i) IgG Fc fragments of fully inhibited development of the PSGN induced by IgG Fc binding strain of emml genotype, (ii) IgG Fc fragments of partially reverted changes caused by the emm12 genotype strain, which was binding only to immune complexes, and (iii) had no effects on pathological changes caused by the emm60 genotype GAS strain, which was binding only IgA.Conclusion. The data obtained point and emergence of differences in mechanisms of renal lesions development at glomerulonephritis, depending on the emm genotype of GAS strain. In addition, it also confirmed GAS-derived involvement for various IgFc-receptor proteins in the pathology. Further studies on potential prophylactic or curative effects of IgG Fc fragments in PSGN should therefore be of interest. The findings might suggest a new therapeutic approach for non-suppurative poststreptococcal diseases.

Portal Vein Thrombosis in a 21-Year-Old Man with Membranoproliferative Glomerulonephritis and Nephrotic Syndrome

Membranoproliferative glomerulonephritis, one of the main causes of nephrotic syndrome, is associated with a state of hypercoagulability that leads to increased risk of thrombotic events. Portosystemic collaterals may reopen due to reversal of the flow within the existing veins and be a presenting feature of thrombosis. We describe a patient who presented with large portosystemic collaterals and signs of portal hypertension and was subsequently found to be affected by membranous proliferative glomerulonephritis. Proteinuria and microscopic haematuria in a patient with signs of portal hypertension and no pre-existing liver disease should raise the suspicion of an underlying kidney disease.

The Frequency of Thromboembolic Complications in Pediatric Nephrotic Syndrome

Background: Nephrotic syndrome (NS) is a common renal disease in the pediatric population, which can be complicated with venous thromboembolic events. Objectives: In the present study, the researchers evaluated the risk factors of venous thrombotic events in children with nephrotic syndrome. Methods: In this descriptive cross sectional study, the researchers evaluated 43 cases of NS including 35 uncomplicated and eight complicated patients with venous thrombotic events, who were admitted to the nephrology ward of Ali-Asghar Children Hospital from 2011 to 2015. Two groups were matched for age onset of NS. Data were recorded on age, gender, body mass index (BMI), histopathologic varieties of NS, and serum albumin level. Results: The mean age of cases with venous thrombotic events was 7.31 ± 4.1 years. There were six females. Of eight cases with venous thrombotic events, five cases suffered of pulmonary thromboembolism (PTE) and five cases of deep vein thrombosis (DVT). The mean serum albumin level in the thrombotic group was 1.87 ± 0.4 g/dL. The histopathologic results showed two cases of membranous proliferative glomerulonephritis (MPGN), three cases of minimal change disease (MCD) and one case of focal segmental glomerulosclerosis (FSGS). The researchers found significant differences between mean serum albumin level and histopathologic results in the case and control groups. Conclusions: Venous thrombosis and pulmonary emboli are important complications in pediatric NS. The risk of VTE increases with lower serum albumin level. The risk of VTE increases with lower serum albumin level. The researchers suggest the use of anti-thrombotic agents as prophylaxis in nephrotic patients with serum albumin level of less than 2 g/dL. Copyright © 2019, Journal of Comprehensive Pediatrics.

Diagnostic Value of Urinary miR-152-5p in Patients with IgA Nephropathy with Elevated Proteinuria Levels.

The current study aims to observe the correlation between the expression of miR-152-5p in urine samples and the condition of IgA nephropathy (IgAN). From January 2017 to October 2017, 40 patients with IgAN, 10 patients with mild glomerular lesions, 10 patients with membranous proliferative glomerulonephritis type I, 10 patients with focal segmental glomeruloscle-rosis, 10 patients with Henoch-Schonlein purpura nephritis, and 10 patients with lupus nephritis. Meanwhile, 25 healthy controls were also included in the physical examination center of our hospital. The expression level of miR-152-5p was detected by RT-qPCR. The correlation between the expression level of miR-152-5p and patholog-ical Haas grading and urinary protein was analyzed. The expression level of miR-152-5p in IgA nephropathy patients was higher than that in other types of glomerulonephritis and healthy control group (p < 0.0001). Meanwhile, the level of miR-152-5p in IgAN patients with high score (p < 0.01) was significantly increased. Furthermore, the level of miR-152-5p was positively corre-lated with the level of urinary protein and the degree of renal pathological damage (r2 = 0.89, p < 0.01). The expression of urinary miR-152-5p is positively correlated with IgA nephropathy, which provides a new way for early diagnosis and treatment of IgA nephropathy with elevated proteinuria.

Recurrence of native kidney disease after kidney transplantation.

The extent of recurrence of original kidney disease after kidney transplantation has been underestimated for several reasons. First, the duration of observation varies among studies. Second, the criteria used to schedule protocol and episode biopsies differ among institutions. And third, diagnostic modalities used for early detection of recurrent original kidney disease also vary. Thus, rates of graft loss attributable to a recurrence of original kidney disease vary among institutions and are often underestimated. However, the recurrence of original disease is often thought to be less important than chronic rejection followed by loss of a functioning allograft. It is important to note that recent data have shown that in patients with certain limited primary kidney diseases (e.g., membranous proliferative glomerulonephritis [MPGN], IgA nephritis [IgAN], focal segmental glomerulonephritis [FSGS], and membranous nephropathy [MN]), the predominant (60%) cause of graft loss is the recurrence of original kidney disease. In addition, the rate of 5-year graft survival in patients with recurrent original kidney disease averages 45%. Thus, research must address the recurrence of original kidney disease. Here we focus on this recurrence and discuss diagnoses, preventive strategies, treatments, and future research directions.

Expression changes of soluble urokinase-type plasminogen activator receptor and soluble triggering receptors expressed by myeloid cell-1 in serum of children with primary nephrotic syndrome and their clinical significance

Objective To investigate the expression changes of soluble urokinase-type plasminogen activator receptor (suPAR) and soluble triggering receptors expressed by myeloid cell-1(sTREM-1) in serum of children with primary nephrotic syndrome(PNS) and their clinical significance. Methods A total of 92 cases of newly diagnosed PNS children were selected in Central Hospital of Yidu Affiliated to Weifang Medical College from June 2014 to September 2016.According to presence or absence of acute tubular necrosis, they were divided into acute renal injury group (27 cases) and non-acute renal injury group (65 cases). According to pathology type, they were divided into mesangial proliferative glomerulonephritis (30 cases), focal segmental glomerulosclerosis (23 cases), membranous nephropathy (18 cases), minimal change disease (14 cases) and membrane proliferative glomerulonephritis (7 cases). In the same period, 45 healthy children were selected as the healthy control group.The clinical data were collected.The serum levels of suPAR and sTREM-1 were measured by adopting enzyme-linked immunosorbent assay (ELISA). Results The levels of total cholesterol(TC), triglycerides(TG), uric acid(UA), urinary protein/creatinine, 24 h urinary protein, urinary N-acetyl-β-glucosaminidase(NAG) and β2-microglobulin(MG) in children with PNS were higher than those in the healthy control group, while serum albumin(ALB) was lower than that in the healthy control group, and the differences were statistically significant (all P<0.05). The serum levels of suPAR and sTREM-1 in PNS patients were (133.09±62.48) ng/L and (79.29±34.68), respectively, which were significantly higher than those in the healthy control group[(31.11±11.61) ng/L and (25.08±8.10) ng/L](t=51.714, 49.435; all P=0.000). The serum levels of suPAR and sTREM-1 in acute renal injury group were (188.82±32.21) ng/L and (109.11±24.78) ng/L, respectively, which were significantly higher than those in non-acute renal injury group [(75.96±28.69) ng/L and (52.23±14.07) ng/L] and healthy control group [(31.11±11.61) ng/L and (25.08±8.10) ng/L] (F=16 739.607, 10 487.256, all P=0.000). The serum levels of suPAR and sTREM-1 in children with focal segmental glomerulosclerosis and membrane proliferative glomerulonephritis were higher than those with minimal change disease, membranous nephropathy and mesangial proliferative glomerulonephritis, and the differences were statistically significant (all P<0.05). Pearson correlation analysis results showed that the serum levels of suPAR and sTREM-1 were positively correlated with TC, TG, urinary protein/creatinine, 24 h urinary protein, urinary NAG and β2-MG (all P<0.05), while negatively correlated with ALB (P<0.05). Conclusions The serum levels of suPAR and sTREM-1 are elevated in children with PNS, and which are related with acute renal injury and pathological type, which can reflect the degree of renal tubular disease and kidney function to a certain extent. Key words: Primary nephrotic syndrome; Soluble urokinase-type plasminogen activator receptor; Soluble triggering receptors expressed by myeloid cell-1; Child

Risk factors for new-onset chronic kidney disease in patients who have received a liver transplant.

The aim of the present study was to analyze the risk factors for new-onset chronic kidney disease (CKD) in patients who have received a liver transplant. A total of 190 patients who underwent liver transplantation between March 2001 and January 2015 were followed up, and analyzed retrospectively. Sex, age, primary disease, preoperative laboratory findings (hemoglobin, albumin, creatinine and glomerular filtration rate), surgical approach, blood loss during the surgery and transfusion volume, postoperative complications, and the average levels of calcineurin inhibitors (CNIs) (from liver transplantation to the onset of CKD) were analyzed. In total, 40 patients developed new-onset CKD after transplantation. Clinical data in the new-onset CKD group were compared with the non-CKD group. A χ2 test, t-test and logistic regression analysis were performed using SPSS 17.0 software. The incidence of new-onset CKD after liver transplantation was 21.1%. Renal pathology included IgA nephropathy, hepatitis B virus-associated nephropathy, membranous proliferative glomerulonephritis, focal segmental glomerular sclerosis and cryoglobulinemia-associated renal injury. Among the CKD patients, 85.7% had tubulointerstitial damage. Univariate analysis showed that preoperative renal function, hemoglobin, intraoperative blood loss and transfusion volume, postoperative acute kidney injury, average levels of CNIs, and hypertension were risk factors for new-onset CKD after liver transplantation. Logistic regression analysis showed that preoperative glomerular filtration rate [odds ratio (OR)=0.980, P=0.041], hemoglobin (OR=0.972, P=0.034), average levels of CNIs (OR=1.364, P=0.015) and hypertension (OR=4.833, P=0.048)] were independent risk factors for new-onset CKD. The incidence of new-onset CKD in patients who received liver transplantation was high. The main risk factors were identified to be preoperative glomerular filtration rate, hemoglobin, postoperative average levels of CNIs and hypertension.

Frequency of familial Mediterranean fever (MEFV) gene mutations in patients with biopsy-proven primary glomerulonephritis.

Primary glomerulopathies are those disorders that affect glomerular structure, function, or both in the absence of a multisystem disorder. We aimed to evaluate the frequency of MEFV gene mutation to show possible coexistence of FMF in patients diagnosed with biopsy-proven primary glomerulonephritis (GN). A total of 64 patients with biopsy-proven primary GN were included in the study. MEFV gene mutations examined retrospectively. The mean age of patients was 39.6±13.4 (range 18-69), 35 of patients were female and 29 of patients were male. Of the 64 patients, 17 were mesangial proliferative glomerulonephritis (MsPGN), 15 were IgA nephropathy (IgAN), 12 were membranous glomerulonephritis (MGN), 11 were focal segmental glomerulosclerosis (FSGS), three were membranous proliferative glomerulonephritis (MPGN), three were immune complex glomerulonephritis (ICGN), two were minimal change disease (MCD), and one was IgM nephropathy (IgMN). MEFV gene mutation was detected in 35.9% (23) of these patients. The most frequently detected mutations were E148Q and M694V. Twelve cases (18.75% of GN patients) with MEFV gene mutation were diagnosed as FMF phenotype I. The frequency of MEFV gene mutation was detected at a high rate of 35.9%. Further studies with larger populations are needed to clarify the importance of these mutations on clinical progression of glomerulonephritis.

Hypocomplementemic Urticarial Vasculitis with Crescentic Glomerulonephritis, Interstitial Nephritis and Small Vessel Vasculopathy: Case Report and Mini- Review

Hypocomplementemic urticarial vasculitis (HUV) is the rare immune complex vasculitis, affecting small vessels and associated with anti-C1q antibodies, presenting with urticaria and hypocomplementemia. Glomerulonephritis, arthritis, obstructive pulmonary disease, and ocular inflammation are common in HUV. HUV may present as an idiopathic disease or be a part of systemic autoimmune or autoinflammatory condition, like systemic lupus erythematosus, arthritis-hives-angioedema (AHA) syndrome, cryoglobulinemic vasculitis, Schnitzler syndrome, Cogan’s syndrome and Muckle–Wells syndrome. Renal involvement includes proteinuria, sometimes of nephrotic range, hematuria and usually moderately impaired kidney function. Various pathology variants were found in patients with HUV: mesagnial proliferative, membranoproliferative, focal proliferative, membranous, minimal change, crescentic and severe sclerosing proliferative glomerulonephritis. Interstitial nephritis and C1q-associated small vessel vasculopathy are poorly described. Here we present a case of HUV with combined renal damage - crescentic glomerulonephritis, interstitial nephritis and small vessel vasculopathy, successfully treated with immunosuppressant’s, and discuss the differential diagnostics of HUV.

NEPHRITOGENIC ACTIVITY OF STREPTOCOCCUS PYOGENES emm1 AND emm12 GENOTYPES ISOLATED FROM PATIENTS AND ASYMPTOMATIC CARRIERS

In this paper the nephritogenic activity of Streptococcus pyogenes genotype emm1 and emm12 clinical isolates from scarlet fever patients and healthy children was considered. As earlier established, strains of these types differ in Fc-binding profile, interacting with native IgG and immune complexes (IC), respectively. As expected, all the type emm1 strains bound native IgG; besides, ICs interacted only with strains from patients but not with those from carriers. In contrast, all type emm12 strains appeared to be negative for native IgG, whereas ICs were bound by strains from patients exclusively. None of the tested strains bound IgG3. By immunization of rabbits, binding of native IgG as well as ICs was associated with increasing of anti-IgG antibodies titer, formation of ICs, «crescent» deposition of IgG and C3-complement, local production of the proinflammatory cytokine TNFα, аnd also with accumulation of lymphocytes in kidney tissue. These signs indicated immune inflammation, leading to experimental membrane-proliferative glomerulonephritis (PSGN). It is known that PSGN development depends on IC-binding by tissue FcγR, on complement activation as well as on tissue infiltration by macrophages/monocytes. According to the data of morphometric evaluation the nephritogenic activity of the type emm12 strains exceeded those of type emm1. On testing of three IC-binding emm12 strains in six rabbits, typical PSGN developed in 5 of them and an abortive process in 1 animal. In case of five IgG-binding type emm1 strains, out of ten rabbits full-blown PSGN was observed only in 3 of them, but abortive changes in 5 and negative result in 2 animals. No pathologic changes were elicited by the «carrier» strains of either genotype; the inability of these to bind ICs, according to literature data, could be explained by mutation in the Mga-regulator gene thereby impeding M-proteins synthesis. We conclude that isolation of type emm12 IC-binding strains at acute streptococcal infection should be considered a high risk-factor for postinfectious sequelae development. The rabbit model of PSGN used in this research thus allowed to reveal some main stages and features of its pathogenesis. 

Primary disease recurrence—effects on paediatric renal transplantation outcomes

Primary disease recurrence after renal transplantation is mainly diagnosed by examination of biopsy samples, but can also be associated with clinical symptoms. In some patients, recurrence can lead to graft loss (7-8% of all graft losses). Primary disease recurrence is generally associated with a high risk of graft loss in patients with focal segmental glomerulosclerosis, membranous proliferative glomerulonephritis, primary hyperoxaluria or atypical haemolytic uraemic syndrome. By contrast, disease recurrence is associated with a limited risk of graft loss in patients with IgA nephropathy, renal involvement associated with Henoch-Schönlein purpura, antineutrophil cytoplasmic antibody-associated glomerulonephritis or lupus nephritis. The presence of systemic diseases that affect the kidneys, such as sickle cell anaemia and diabetes mellitus, also increases the risk of delayed graft loss. This Review provides an overview of the epidemiology, pathophysiology and management of primary disease recurrence in paediatric renal graft recipients, and describes the overall effect on graft survival of each of the primary diseases listed above. With appropriate management, few paediatric patients should be excluded from renal transplantation programmes because of an increased risk of recurrence.