Mesangial Electron-dense Deposits Research Articles

#2864 IgA dominant post-infectious glomerulonephritis secondary to the infected left ankle joint in a non-diabetic patient, a case report

Abstract Introduction Post-infectious glomerulonephritis (PIGN) is an immune complex glomerulonephritis that commonly affects children and young adults following beta haemolytic Streptococcal throat or skin infections. Kidney biopsy is characterised by Segmental or global endocapillary hypercellularity, and crescents may be present. In immunofluorescence, post-infectious glomerulonephritis typically shows IgG and C3 deposition. A rare type of PIGN is IgA-dominant post-infection glomerulonephritis. It commonly occurs in the setting of active infection. It usually presents in patients > 60 years old with diabetes mellitus, alcohol consumption, and Staphylococcal infections. It can present with RPGN, AKI, and nephrotic syndrome. Hypocomplementemia can be present, and immunofluorescence is characterised by IgA dominance with C3 co-dominance and no IgG. Despite the strong association with Staph aureus, however, it has been reported with other types of infections. The main line of treatment is antibiotic eradication of the infection. Steroids can be used based on the severity of the lesion and the presence of crescents. Its prognosis is worse than that of the traditional PIGN. In this case, we report a case of IgA-dominant post-infectious glomerulonephritis secondary to left ankle osteomyelitis with Staph aureus infection. Case Presentation A 65-year-old lady had open reduction and internal fixation of a left trimalleolar ankle fracture in June 2023 at a district general hospital. Unfortunately, the post-operative course was complicated by wound infection. The wound swab showed Heavy growth of Staphylococcus aureus. This was followed by Acute Kidney Injury (AKI) stage 3; therefore, she was transferred from her hospital to our renal ward. On admission to the ward, her creatinine was 388 μmol/L(baseline creatinine was 73 μmol/L one month before admission), urine dipstick was positive for blood and protein, and urine protein creatinine ratio was 480 mg/mmol. She had only a medical background of bronchial asthma for which she was only on Inhalers (Beta Agonist) as a regular medication. CT scan of the left ankle revealed appearances consistent with osteomyelitis of both the lateral and medial malleoli. This finding was discussed with microbiology and orthopaedic teams, and the patient was started on intravenous antibiotics (Vancomycin followed by doxycycline). A kidney biopsy was done. Mesangial electron-dense deposits were identified. Immunohistochemistry revealed IgA dominant, predominantly mesangial positivity, with associated C3. The picture was consistent with IgA acute glomerulonephritis associated with S. aureus, which is a post-infectious Glomerulonephritis with dominant IgA staining (rather than conventional IgA nephropathy). With proper intravenous hydration and antibiotics, her inflammatory markers started to improve, and her renal chemistry followed the inflammatory markers, and her last creatinine improved to 146 μmol/L, eGFR 31 ml/min and UPCR was 40 mg/mmol. Discussion IgA-dominant post-infectious glomerulonephritis is now a distinct form of PIGN, which usually presents with acute kidney injury, haematuria, and proteinuria and is typically related to Staph aureus infection. In contrast to typical IgA nephropathy, there is no role for steroid or immunosuppression in the treatment of IgA-dominant post-infectious glomerulonephritis, and the treatment is mainly dependent on the treatment of infection.

Liver factor B silencing to cure C3 glomerulopathy: Evidence from a mouse model of complement dysregulation

Uncontrolled activation of the alternative pathway (AP) of complement, due to genetic and/or acquired defects, plays a primary pathogenetic role in C3 glomerulopathy (C3G), a rare and heterogeneous disease characterised by predominant C3 fragment deposition within the glomerulus, as well as glomerular damage. There are currently no approved disease-specific treatments for C3G, but new drugs that directly counteract AP dysregulation, targeting components of the pathway, have opened promising new perspectives for managing the disease.Complement factor B (FB), which is primarily synthesised by hepatocytes, is a key component of the AP, as it drives the central amplification loop of the complement system. In this study we used a GalNAc (N-Acetylgalactosamine)-conjugated siRNA to selectively target and suppress liver FB expression in two mouse models characterised by the complete (Cfh-/- mice) or partial (Cfh+/-) loss of function of complement factor H (FH). Homozygous deletion of FH induced a severe C3G phenotype, with strong dysregulation of the AP of complement, glomerular C3 deposition and almost complete C3 consumption. Mice with a heterozygous deletion of FH had intermediate C3 levels and exhibited slower disease progression, resembling human C3G more closely.Here we showed that FB siRNA treatment did not improve serum C3 levels, nor limit glomerular C3 deposition in Cfh-/- mice, while it did normalise circulating C3 levels, reduce glomerular C3 deposits, and limit mesangial electron-dense deposits in Cfh+/- mice. The present data provide important insights into the potential benefits and limitations of FB-targeted inhibition strategies and suggest RNA interference-mediated FB silencing in the liver as a possible therapeutic approach for treating C3G patients with FH haploinsufficiency.

#4488 OLD BIOPSY IS ALWAYS GOLD, REVISING MEMBRANOPROLIFERATIVE GN DIAGNOSIS IN A RENAL TRANSPLANT PATIENT

Abstract Background and Aims MPGN resulting from hepatitis C virus (HCV) infection typically shows granular deposition of immunoglobulin M (IgM), C3, and both kappa and lambda light chains. Immunoglobulin G (IgG) may or may not be present, and C1q is typically negative, the same pathology can be found in other viral infections. The recurrence rate post-transplantation is high, with 33% of immune-complex MPGN. Graft loss is even higher 65%, especially among patients with idiopathic MPGN. Treatment of a patient with significant proteinuria can be tricky, as no proven treatment is described yet, but plasmapheresis and induction with cyclophosphamide were described for heavy proteinuria >3.5 g/day. Method 79 year old female patient, known case of live unrelated renal transplantation in December 2013, primary renal disease is unknown. She had a history of equivocal hepatitis C virus antibodies, but Hepatitis C virus RNA was not detected. She is also known to have Type II Diabetes Mellitus and hypertension. The patient had baseline creatinine of 100-120 micromol/L. 24 hr urine protein was 0.8 g/Day but started rising quickly to reach a peak of 9.2 g/g seven months post-transplantation to nephrotic range proteinuria but her serum albumin level was always above 35 g/L. Serum protein electrophoresis showed no M band, a kappa/ Lambda ratio 1.21 within a normal range (0.260-1.65). Anti- nuclear antibody (ANA), P-ANCA, C-ANCA, and Double-stranded DNA all were negative. Complements were within normal range C3 1.39 g/L (0.79 -1.52), C4 0.44 g/L(0.17-0.57)m rheumatoid factor and Anti- citrullinated peptide antibodies were negative. Hepatitis b Virus surface antigen and core antibodies were not reactive, HIV screening was negative. Urine analysis showed RBCs but no RBC casts. Renal biopsy showed mild mesangial expansion and mild l increase in mesangial cells and matrix. Some glomeruli show increased lobulation with increase in mesangial cells and matrix with segmental endocapillary proliferation There is double contour of the glomerular basement membrane with scattered spikes and holes within the basement membrane seen best with silver stain. There is mild increase in the thickness of glomerular basement membrane. There is focal mild lymphocytic infiltration. Tubulitis is not seen in the examined material. One Focal area of mild interstitial fibrosis. Sampled blood vessels are unremarkable. The stain for C4d is negative. Immunofluorescence showed granular capillary wall immunoreactivity to IgM (+2), C4 (+1), C1q (+1), and Lambda light chain (+2). The glomeruli show no immunoreactivity to IgG, IgA, C3, Kappa and fibrin. The glomeruli show (+) staining for albumin. Tubular protein reabsorption droplets showed immunoreactivity for albumin, IgG, IgM, C3, kappa and lambda light chains. Electron microscopy showed many subendothelial, and mesangial electron-dense deposits. The patient was on maintenance immunosuppression medications inform of mycophenolic acid 720 mg, cyclosporine; 250mg BID, and Prednisolone 5 mg daily.Revisiting the new classification of membranoproliferative glomerulonephritis is challenging in this patient, since there is the dominance of IgM deposition by immunofluorescence and C4 but not C3 makes it challenging, the negative monoclonal band in serum electrophoresis and negative autoimmune workup excludes immune complex mediate MPGN, leave idiopathic MPGN a possibility, keeping in mind that hepatitis C virus infection was never confirmed. On the other hand, IF showed IgM with C4 subendothelial and mesangial dense deposits that excludes away the C4 glomerulopathy. Results Whether this is a recurrence of glomerular disease early on post-transplantation or denovo membranoproliferative disease, she responded well to the addition of losartan 100 mg daily, with a reduction of her urinary protein to less than 1 g/g. the patient never received treatment for the hepatitis C virus. Conclusion In our patient, it is difficult to conclude if the cause of MPGN is recurrence or denovo GN, especially with severe proteinuria that responded well to ACEi treatment. The pathological findings can be tricky.

Rapidly progressive IgA nephropathy with membranoproliferative glomerulonephritis-like lesions in an elderly man following the third dose of an mRNA COVID-19 vaccine: a case report

BackgroundAs messenger RNA (mRNA)-based vaccines for coronavirus disease 2019 (COVID-19) have been administered to millions of individuals worldwide, cases of de novo and relapsing glomerulonephritis after mRNA COVID-19 vaccination are increasing in the literature. While most previous publications reported glomerulonephritis after the first or second dose of an mRNA vaccine, few reports of glomerulonephritis occurring after the third dose of an mRNA vaccine currently exist.Case presentationWe report a case of rapidly progressive glomerulonephritis in a patient following the third dose of an mRNA COVID-19 vaccine. A 77-year-old Japanese man with a history of hypertension and atrial fibrillation was referred to our hospital for evaluation of anorexia, pruritus, and lower extremity edema. One year before referral, he received two mRNA vaccines (BNT162b2) for COVID-19. Three months before the visit, he received a third mRNA vaccine (mRNA-1273) for COVID-19. On admission, the patient presented severe renal failure with a serum creatinine level of 16.29 mg/dL, which had increased from 1.67 mg/dL one month earlier, prompting us to initiate hemodialysis. Urinalysis showed nephrotic-range proteinuria and hematuria. Renal biopsy revealed mild mesangial proliferation and expansion, a lobular appearance, and double contours of the glomerular basement membrane. Renal tubules had severe atrophy. Immunofluorescence microscopy showed strong mesangial staining for IgA, IgM, and C3c. Electron microscopy exhibited mesangial and subendothelial electron-dense deposits, leading to a diagnosis of IgA nephropathy with membranoproliferative glomerulonephritis-like changes. The kidney function remained unchanged after steroid therapy.ConclusionsAlthough the link between renal lesions and mRNA vaccines remains unclear, a robust immune response induced by mRNA vaccines may play a role in the pathogenesis of glomerulonephritis. Further studies of the immunological effects of mRNA vaccines on the kidney are warranted.

Therapeutic Small Interfering RNA Targeting Complement C3 in a Mouse Model of C3 Glomerulopathy.

Alternative pathway complement dysregulation with abnormal glomerular C3 deposits and glomerular damage is a key mechanism of pathology in C3 glomerulopathy (C3G). No disease-specific treatments are currently available for C3G. Therapeutics inhibiting complement are emerging as a potential strategy for the treatment of C3G. In this study, we investigated the effects of N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) targeting the C3 component of complement that inhibits liver C3 expression in the C3G model of mice with heterozygous deficiency of factor H (Cfh +/- mice). We showed a duration of action for GalNAc-conjugated C3 siRNA in reducing the liver C3 gene expression in Cfh +/- mice that were dosed s.c. once a month for up to 7 mo. C3 siRNA limited fluid-phase alternative pathway activation, reducing circulating C3 fragmentation and activation of factor B. Treatment with GalNAc-conjugated C3 siRNA reduced glomerular C3d deposits in Cfh +/- mice to levels similar to those of wild-type mice. Ultrastructural analysis further revealed the efficacy of the C3 siRNA in slowing the formation of mesangial and subendothelial electron-dense deposits. The present data indicate that RNA interference-mediated C3 silencing in the liver may be a relevant therapeutic strategy for treating patients with C3G associated with the haploinsufficiency of complement factor H.

Renal Abnormalities Caused by Canine Distemper Virus Infection in Terminal Patients.

The aim of this study was to analyze the glomerular and tubular alterations in dogs with terminal distemper through light microscopy, immunofluorescence, and electron microscopy. Thirteen animals with a molecular diagnosis of distemper and neurological signs were selected. As a control group, 10 clinically healthy animals with no manifestations or signs of disease and with negative tests for Ehrlichia sp., Anaplasma sp., and Babesia sp. were included in this study. Renal tissue was evaluated by light microscopy, topochemistry for DNA/chromatin, and video image analysis to detect the nuclear phenotypes of the renal tubular epithelial cells (RTECs), immunofluorescence, and transmission electron microscopy. Results showed that dogs with distemper exhibited anemia, hypergammaglobulinemia, and proteinuria. Creatinine in the distemper group was lower compared to the control group (p = 0.0026), but there was no significant difference in relation to urea (p = 0.9876). Although this alteration may be due to the smaller muscle mass observed in animals with distemper, it probably is not of clinical importance. Glomerular and tubular lesions were confirmed by light microscopy in 84.6% of these animals. Additional findings in the animals with distemper included deposition of different classes of immunoglobulins, particularly IgM in 92.3% of the cases, fibrinogen deposition in 69.2% of the cases as assessed by immunofluorescence, alterations in the nuclear phenotypes of the RTEC characterized by condensation of chromatin, loss of DNA and reduction in the nuclear shape, and the presence of subendothelial and mesangial electron-dense deposits. These findings confirm the existence of renal alterations related to terminal distemper.

Clinical case of fibronectin glomerulopathy

Fibronectin glomerulopathy (FNGP) is an extremely rare glomerulopathy with an autosomal dominant pattern of inheritance. Sporadic cases of the disease are also described. Currently, several types of FN1 gene mutations are known that underlie conformational changes in the fibronectin molecule and lead to its deposition in the renal tissue. The clinical manifestations of FNGP may be very heterogeneous, but in most cases are characterized by proteinuria, microscopic hematuria, arterial hypertension, and long-term progressive renal failure. Renal biopsy is the main method for diagnosing the disease. Histologically, GFND is characterized by a lobular glomerular architecture with mesangial expansion and obliteration of capillary loops due to the accumulation of an acellular, periodic acid–Schiff positive, silver Jones-negative material. Immunofluorescence is usually negative. Electron microscopy shows finely granular or fibrillary mesangial and subendothelial electron-dense deposits. At higher magnifications, the fibrils have a diameter of 12-16 nm and are randomly arranged. Standard protocols for the etiopathogenetic therapy of FNGP are not currently developed. Improvement of clinical status and prognosis can be achieved by optimizing blood pressure and proteinuria control by renin–angiotensin–aldosterone system blockers. The recurrence risk of FNGP after renal transplantation remains uncertain due to the rare prevalence of the pathology. In this article, we report a 25-year-old man with nephrotic syndrome, which occurred after a previous upper respiratory tract infection. Histological changes specific to FNGP were found in the kidney biopsy. Genetic analysis was not performed. The absence of a family history of kidney disease suggests that this is a sporadic case of FNGP.

The Prevalence of Mesangial Electron-Dense Deposits in PLA2R-Positive Membranous Nephropathy

Introduction: Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults and can be primary or secondary. The antigenic target of antibodies in 70% of primary cases is phospholipase A2 receptor (PLA2R). The presence or absence of mesangial electron-dense deposits has been used to distinguish between primary and secondary MN. Mesangial deposits suggest MN due to lupus, infection, or other causes, though they are reported to occur in approximately 10% of primary MN. Staining for PLA2R is now frequently used for confirming a diagnosis of primary MN. If mesangial deposits predict a secondary cause, they should be more frequent in PLA2R-negative biopsies. Methods: A review of institutional kidney biopsies between March 2017 and June 2020 identified all cases of MN. Cases with a diagnosis of lupus or near “full-house” staining by immunofluorescence microscopy (IF) were excluded. Light microscopy, IF, and electron microscopy (EM) were performed. PLA2R staining was performed by IF. EM for all cases was reviewed and electron-dense deposit location, distribution, and size were determined. Results: Ninety-three cases of MN were identified, of which 86 had both PLA2R staining and EM performed. Of these, 51 cases (59%) were positive for PLA2R and 35 (41%) were negative. Mesangial electron-dense deposits were present in 22 (25.6%) of the 86 cases, including 27.5% (14/51) of PLA2R-positive cases and 22.8% (8/35) of PLA2R-negative cases. No difference was seen in size or distribution of deposits, or other features considered suggestive of secondary MN. Conclusion: PLA2R-negative cases were not more likely to have mesangial deposits than PLA2R-positive cases. Mesangial deposits should not be used as an indicator of secondary MN.

A Donor With Green Kidneys—To Transplant or Not to Transplant: A Case Report

A Donor With Green Kidneys—To Transplant or Not to Transplant: A Case Report

POS-722 SPECTRUM OF RENAL ALLOGRAFT BIOPSY – A SINGLE CENTRE EXPERIENCE

Histopathology plays a key role in diagnosis of graft dysfunction in transplant recipients. Apart from graft rejection, many patients are having recurrence of native kidney disease and infections causing graft dysfunction. In this study, we would like to describe the different histopathological profile of transplant kidney biopsy in our centre. We had conducted a retrospective descriptive study of all transplant kidney biopsies which were performed between Jan 2014 to Nov 2020 in a tertiary care hospital. From the registry, age, sex, duration since transplant and histopathological diagnosis were collected and analysed. Total number of biopsies performed were 587 in the past seven years. Males were 81.3% (n=477). Patients with age less than 20 were 4.9% (n=29), 21 to 40 years were 75.2% (n=441) and 41 to 60 years were 19.9% (n=117). None of them were more than 60 years of age. Duration since transplant was analysed for these biopsies. Patients with less than 1 month, 1month to 3 months, 3 months to 1 year and more than 1 year were 180 (30.6%), 92 (15.7%), 120 (20.4%) and 195 (33.2%) respectively. Due to the presence of multiple pathologies in a biopsy, a total of 649 pathologies were found. Cellular and humoral rejections were 32.2% and 13.6% respectively. Across these timelines since transplant, cell mediated rejections (CMR) (34.5%, n=72) and antibody mediated rejections (ABMR) (50%, n=44) were more seen during >1 year post transplant. Apart from these, incidence of glomerular, interstitial and vascular pathologies found which were described in table 1 below. IgA Nephropathy and Thrombotic Microangiopathy (TMA) were most seen glomerular pathology (n=19,2.9%) followed by Focal segmental glomerulosclerosis (FSGS) (n=17,2.6%). Crescentic IgA Nephropathy was seen in 2 patients who had IgA Nephropathy as native kidney disease. 2,8-Dihydroxy Adenine Crystalline (DHA) Nephropathy was diagnoed at 10 months post transplant in one patient whose native kidney disease was not known. Out of 587 biopsies, 9 were preimplantation and 12 were followup protocol biopsies. In the preimplantation biopsy, 6 were normal and 3 were Acute Tubular Injury (ATI). Special stains for SV 40 and CMV were used in 14 and 2 patients respectively. Two patients had SV 40 and one had CMV positivity among them. Electron microscopy was done in 6 patients. Four of them had diffuse effacement of podocyte foot processes whereas, in light microscopy 3 had minimal change pattern of injury and one had FSGS. One had subepithelial and mesangial electron dense deposits with Membranoproliferative Glomerulonephritis(MPGN) in light microsopy and the other had mesangial electron dense deposits / effacement of foot processes of podocyte with IgA Nephropathy / Collapsing Glomerulopathy in light microscopy. Complications encountered post biopsy were perinephric hematoma and hematuria. One patient with perinephric hematoma had blood clots passed in urine which caused hydroureteronephrosis and then resolved with conservative management. In our series, CNI Toxicity was seen in 26.8% (n=174), Infection in 4.2% (n=27), Rejection in 46.8% (n=304), Glomerulonephritis in 12.2% (n=79) and other pathologies in 10% (n=65) of the allograft biopsies performed.

Characteristics of patients with coexisting DNAJB9-associated fibrillary glomerulonephritis and IgA nephropathy.

BackgroundCoexistence of fibrillary glomerulonephritis (FGN) and immunoglobulin A (IgA) nephropathy (IgAN) in the same kidney biopsy (FGN–IgAN) is rare, and the clinicopathologic characteristics and outcome of this dual glomerulopathy are unknown.MethodsIn this study, 20 patients with FGN–IgAN were studied and their characteristics were compared with 40 FGN and 40 IgAN control patients.ResultsConcurrent IgAN was present in 1.8% of 847 consecutive FGN cases and was the second most common concurrent glomerulopathy after diabetic nephropathy. FGN–IgAN patients were overwhelmingly White (94%) and contrary to FGN patients were predominantly (60%) males. Compared with IgAN patients, FGN–IgAN patients were older, had higher proteinuria, a higher incidence of renal insufficiency, and a lower incidence of microhematuria and gross hematuria at diagnosis. Six (30%) patients had malignancy, autoimmune disease or hepatitis C infection, but none had a secondary cause of IgAN or clinical features of Henoch–Schonlein purpura. Histologically, all cases exhibited smudgy glomerular staining for immunoglobulin G and DnaJ homolog subfamily B member 9 (DNAJB9) with corresponding fibrillary deposits and granular mesangial staining for IgA with corresponding mesangial granular electron-dense deposits. On follow-up (median 27 months), 10 of 18 (56%) FGN–IgAN patients progressed to end-stage kidney disease (ESKD), including 5 who subsequently died. Serum creatinine at diagnosis was a poor predictor of renal survival. The proportion of patients reaching ESKD or died was higher in FGN–IgAN than in IgAN. The median Kaplan–Meier ESKD-free survival time was 44 months for FGN–IgAN, which was shorter than IgAN (unable to compute, P = 0.013) and FGN (107 months, P = 0.048).ConclusionsFGN–IgAN is very rare, with clinical presentation and demographics closer to FGN than IgAN. Prognosis is guarded with a median renal survival of 3.6 years. The diagnosis of this dual glomerulopathy requires careful evaluation of immunofluorescence findings, and electron microscopy or DNAJB9 immunohistochemistry.

Comparison of Ultrastructural Features Between Patients with Mercury-associated Membranous Nephropathy and Idiopathic Membranous Nephropathy

BackgroundProlonged exposure to mercury can cause membranous nephropathy. Mercury-associated membranous nephropathy (M-MN) and idiopathic membranous nephropathy (I-MN) have similar clinical manifestations, making misdiagnoses likely. We compared the clinicopathological and ultrastructural features of M-MN and I-MN. MethodsWe retrospectively analyzed the clinicopathological data of 13 M-MN patients and 13 I-MN patients. Electron micrographs of glomerular capillaries were taken, and foot process width (FPW) and the number of foot processes per 10 μm glomerular basement membrane (GBM) were calculated. The presence and location of electron-dense deposits were recorded. ResultsCompared with I-MN patients, M-MN patients were younger (38.7 ± 8.5 versus 45.8 ± 5.7 years, P = 0.020), achieved complete remission more quickly (9.0 ± 6.1 versus 20.3 ± 9.8 months, P = 0.004), and had a lower relapse rate (0 versus 45.5%, P = 0.014). Patients with M-MN also had lower FPW (974.3 [interquartile range or IQR, 791.2–1504.4] nm versus 2370.6 [IQR, 2219.4–2559.1] nm, P = 0.001), more foot processes per 10 μm GBM (8.1 [IQR, 5.2–10.0] versus 3.3 [IQR, 3.1–3.5], P = 0.001), and a higher rate of mesangial electron-dense deposits (41.7% versus 0, P = 0.015). A cut-off FPW of <1654 nm differentiated M-MN from I-MN with high sensitivity (92.3%) and specificity (83.3%). ConclusionsFoot process effacement was less severe in M-MN than in I-MN. In patients with mercury toxic exposure, MN with less severe foot processes effacement suggested mercury could be the cause. Better prognosis in patients with M-MN may be associated with minor podocyte damage.

Clinicopathological study of mixed cryoglobulinemic glomerulonephritis secondary to hepatitis B virus infection

BackgroundCryoglobulinemic glomerulonephritis (CryoGn) caused by hepatitis B virus (HBV) infection was rarely reported. Our study aimed to investigate the clinical features, renal pathology findings, and prognosis in patients with HBV related CryoGn.MethodsThis was a retrospective study including seven Chinese patients with HBV related CryoGn in a tertiary referral hospital from April 2016 to March 2019. The clinical and pathological data were collected and analyzed.ResultsAge at renal biopsy was 47 ± 12 years, with female/male ratio 3/4. Urine protein was 5.6 (3.0, 6.6) g/d and five cases presented with nephrotic syndrome. The baseline eGFR was 23.5 (20.2, 46.3) ml/min per 1.73m2. The extrarenal manifestations included purpura (n = 6), arthralgia (n = 1), peripheral neuropathy (n = 1), and cardiomyopathy (n = 1). Six cases had type II cryoglobulinemia with IgMκ, the other one had type III. The median cryocrit was 4.0 (1.0, 15.0) %. Renal pathologic findings on light microscopy: endocapillary proliferative glomerulonephritis (Gn) (n = 3), membranoproliferative Gn (n = 3), and mesangial proliferative Gn (n = 1). On immunofluorescence microscopy, the predominant type of immunoglobulin deposits was IgM (n = 5). HBsAg and HBcAg deposits were found in one case. Ultrastructural studies showed granular subendothelial and mesangial electron-dense deposits in all patients and microtubules in one case. All patients received antiviral medications. They were given corticosteroid alone (n = 2) or combined with cyclophosphamide (n = 4) or mycophenolate mofetil (n = 1). Two patients received plasmapheresis. The median follow-up time was 18 (6, 37) months. Four patients got remission, two patients died of pneumonia, and one progressed to end-stage renal disease (ESRD). At endpoint of follow-up, 24hUP was 2.1 (0.8–5.2) g/d, and eGFR was 55.3 (20.7, 111.8) ml/min per 1.73m2. The median cryocrit decreased to 1.0 (0, 5.75) %.ConclusionsThe etiology of mixed CryoGn should be screened for HBV infection. Endocapillary proliferative Gn and membranoproliferative Gn were the common pathologic patterns. Diagnosis and treatment in early stage benefit patients’ renal outcomes. Immunosuppressive therapy should be considered for severe renal disease, based on efficient antiviral therapy.

P0477CLINICOPATHOLOGICAL STUDY OF MIXED CRYOGLOBULINEMIC GLOMERULONEPHRITIS SECONDARY TO HEPATITIS B VIRUS INFECTION

Abstract Background and Aims To describe the clinical features, renal pathology findings and prognosis in patients with mixed cryoglobulinemic glomerulonephritis (Gn) caused by hepatitis B virus (HBV) infection. Method This was a retrospective study including seven Chinese patients with HBV infection associated mixed cryoglobulinemic Gn in a tertiary referral hospital from April, 2016 to March, 2019. The demographic, clinical, pathological characteristics, treatment and follow-up data were collected and analyzed. Results Age at renal biopsy was 47±12 years, including three females and four males. 24hUP was 5.6(3.0, 6.6)g/d and five cases presented with nephrotic syndrome. The median baseline eGFR(CKD-EPI) was 23.5(20.2, 46.3) ml/min per 1.73m2. The extrarenal manifestations were: purpura (n=6), arthralgia (n=1), peripheral neuropathy (n=1), and cardiomyopathy (n=1). Six cases had type II cryoglobulinemia with IgMκ, the other one had type III. The median cryocrit was 4.0 (1.0, 15.0) %, rheumatoid factor was 368(117, 733) IU/ml, C3 was 0.48(0.41, 0.57) g/L, C4 was 0.013(0.003, 0.118) g/L. Renal pathologic findings on light microscopy: endocapillary proliferative Gn (n=3), membranoproliferative Gn (n=3), and mesangial proliferative glomerulonephritis(n=1). Hyaline thrombi were seen in four cases, while crescents were found in two cases. On immunofluorescence microscopy, the predominant types of immunoglobulin deposits were: IgM(n=5), IgA(n=1), and codominance of IgG and IgA(n=1). HBsAg and HBcAg deposits were found in only one case. Ultrastructural studies showed granular subendothelial and mesangial electron-dense deposits in all patients and organized microtubules was seen in only one case. All patients received antiviral medication (entecavir, n=6; lamivudine, n=1). They were given corticosteroid alone(n=2) or combined with cyclophosphamide(n=4) or mycophenolate mofetil(n=1). Two patients received plasmapheresis. The median follow-up time were 18 (6, 37) months. One patient died from pneumonia, and one progressed to end stage of renal disease (ESRD). At endpoint of follow-up, 24hUP was 2.1 (0.8-5.2) g/d, and eGFR (CKD-EPI) was 55.3 (20.7, 111.8) ml/min per 1.73m2. Conclusion Mixed cryoglobulinemic Gn should be screened for HBV etiologies, especially in HBV-endemic country. Endocapillary proliferative Gn was the common pathologic type, as well as membranoproliferative Gn. Diagnosis and treatment in early stage benefit patients’ renal outcome. Long-term prognosis should be investigated in further studies.

P0128COMPARISON OF ULTRASTRUCTURE FEATURES BETWEEN PATIENTS WITH MERCURY-ASSOCIATED MEMBRANOUS NEPHROPATHY AND IDIOPATHIC MEMBRANOUS NEPHROPATHY

Abstract Background and Aims Prolonged exposure to mercury can cause membranous nephropathy. The routine clinicopathological features of mercury-associated membranous nephropathy (M-MN) and idiopathic membranous nephropathy (I-MN) are similar. The difference in ultrastructure between them was observed clinically. The current study retrospectively compared the ultrastructure features, clinical and pathological data, treatment and prognosis of patients with M-MN and I-MN. Method Thirteen patients with M-MN and 13 patients with I-MN were enrolled. The clinical and pathological data were retrospectively collected. Electron micrographs of glomerular capillaries were taken and the foot process width (FPW) and the number of foot processes per 10 μm glomerular basement membrane (GBM) were measured. The presence and location of electron-dense deposits in mesangium and subendothelial region were recorded. Results Patients with M-MN were younger (38.7±8.5 versus 45.8±5.7 years, P=0.020), with a shorter duration of complete remission (9.0±6.1 versus 20.3±9.8 months, P=0.004) and lower relapse rate (0% versus 45.5%, P=0.014) than patients with I-MN. As to ultrastructure, patients with M-MN had lower levels of FPW [974.3nm (range 791.2∼1504.4) versus 2370.6nm (range 2219.4∼2559.1), P=0.001, Figure 1], more foot processes per 10 μm GBM [8.1 (range 5.2∼10.0) versus 3.3 (range 3.1∼3.5), P=0.001], and higher ratio of mesangial electron-dense deposits (41.7% versus 0, P=0.015, Figure 2) than those with I-MN. Multivariate analysis showed that type of disease (M-MN or I-MN) and stage of MN (stageIor stageIIand above) were the two only determinants of FPW. FPW over 1645 nm differentiated M-MN from I-MN with high sensitivity (92.3%) and specificity (83.3%). Conclusion The quantitative analysis of foot processes may offer a potential tool to distinguish M-MN from I-MN. Better prognosis in patients with M-MN may be related to minor podocyte damage.

SUN-389 Collagenofibrotic glomerulopathy in kidney transplant recipient: A first report

Collagenofibrotic glomerulopathy (CG) also known as collagen type 3 glomerulopathy is a rare disease characterized by the deposition of collagen type 3 in the glomeruli. The absence of skeletal abnormalities in these patient is one feature that helps in distinguishing CG from nail patella syndrome, another collagen type 3 deposition disease in renal glomeruli. High serum levels of pro-collagen type III peptide were reported in this disease. Patients may have proteinuria, hematuria and/or renal dysfunction. CG is considered a progressive disease with variable rate of progression. CG manifests as membranoproliferative pattern of injury by light microscopy with negative immunofluorescence. The definitive diagnosis is made by electron microscopy with the characteristic subendothelial and mesangial curved and comma-like banded collagen type 3 fibers of 45-65 nm in periodicity. A retrospective chart review of collagenofibrotic glomerulopathy case at the American University of Beirut Medical Center. A 39 years-old man had a living-related kidney transplant 13 years ago for unknown cause ESKD. An allograft biopsy was performed for rise in creatinine and proteinuria without hematuria. He has been maintained on cyclosporine, azathioprine and prednisone for 12 years before a switch to tacrolimus, mycophenolate mofetil (MMF) and prednisone one year, done prior for a rise in creatinine at an outside hospital. He was diagnosed with hypertension and diabetes mellitus three years prior to biopsy. His family history is negative for renal disease.Table 1Laboratory values at the time of kidney biopsyCreatinine1.8-2.2 mg/dlTacrolimus4.624 hours urine protein1.2 grams24 hours urine albumin0.65 gramsHbA1c7.8 %HIV serologyNegativeHepatitis B and C serologyNegativeUrinalysis+ 2 proteinuria, negative hematuria Open table in a new tab Table 2Pathologic FindingsLight microscopy (LM), figure 1 (H&E x400).Mesangial matrix expansion and hypercellularity, endocapillary hypercellularity, thickened glomerular capillary wall and focal double contour formation.Immunofluorescence (IF)Negative for IgA, IgG, IgM, C3, C4, C1q, kappa and lambda.Electron microscopy (EM) figure 2Accumulation of collagen fibers between the capillary basement membranes and swollen endothelial cells, with increased mesangial matrix deposition. Tubules show tubular injury with cytoplasmic vacuolization. No subepithelial, subendothelial or mesangial electron dense deposits are identified. The capillary loops are patent. Open table in a new tab Figure 2View Large Image Figure ViewerDownload Hi-res image Download (PPT) We are reporting the first case of post-transplant Collagenofibrotic glomerulopathy (CG). The recurrence post-transplant points towards a systemic disease process, including genetic predilection. It highlights the importance of considering unrecognized kidney disease causes in patients with unknown cause ESKD.

An unusual pattern of peritubular capillary injury involving apoptosis in a renal transplant patient

ABSTRACTMicrovascular injury is an important factor in renal allograft survival. Repeated episodes of endothelial injury from chronic antibody-mediated rejection typically manifest at the ultrastructural level as circumferential multilayering of remodeled glomerular basement membrane material and peritubular capillary basal lamina. In contrast to this typical pattern of microvascular injury, a renal transplantation case is presented in which focally dilated and multilayered segments of peritubular capillary basal lamina bearing lipid droplets were interspersed with ultrastructurally normal unilayered segments of basal lamina devoid of lipid droplets. Glomerular basement membranes were not affected by this process. The peak incidence of lipid droplets within the peritubular capillary walls coincided with a peak in apoptotic activity within the allograft. Lesser amounts of the same lipidic material were identified in the mesangial matrix and an arteriolar wall. Mesangial electron-dense deposits were detected at two weeks posttransplantation and their appearance coincided with elevated immunological activity in the glomeruli, as determined by immunofluorescence microscopy. The unusual ultrastructure and immunological activity observed in this case may reflect a process of impaired apoptotic clearance within the allograft. The six biopsies from a single patient are discussed in the setting of a highly sensitized renal transplant recipient who received prophylactic terminal complement blockade by eculizumab. The findings may be relevant to the study of apoptosis, efferocytosis, microvascular injury, eculizumab, rejection, lupus, and drug-related disease.

Poststreptococcal glomerulonephritis with atypical hemolytic uremic syndrome: An unusual presentation

A 14-year-old female presented with oliguric dialysis requiring kidney injury due to acute poststreptococcal glomerulonephritis (PSGN) with hypertension strongly suggestive of atypical hemolytic uremic syndrome (aHUS) with microangiopathic hemolytic anemia and elevated factor H antibody levels. Renal biopsy revealed crescentic glomerulonephritis with typical subepithelial, intramembranous and mesangial electron-dense deposits (humps) on electron microscopy. She was treated with glucocorticoids following which she recovered, remained dialysis free and her Factor H antibody levels and depressed complement 3 levels normalized. PSGN-associated HUS has rarely been described, with this patient being the 11th case reported, to the best of our knowledge. This case is unique as we describe the course and management of the first patient with PSGN-associated HUS in the era of eculizumab, without eculizumab, and plasmapheresis. This patient presented with clinical and histological features of PSGN as well as anemia and thrombocytopenia consistent with aHUS. Given that these diseases are both mediated through the alternate complement pathway, it is tempting to speculate that blockade of the terminal complement pathway through the use of eculizumab might improve outcomes. Temporally, the hematological parameters in our patient seemed to improve soon after treatment was initiated; however, none of the prior cases in the literature experienced any long-term hematological issues, suggesting that supportive management can be a reasonable alternative.

Thrombotic microangiopathy mimicking membranoproliferative glomerulonephritis.

A 4-year-old boy presented with proteinuria and developed progressive renal failure over 6 years. In the patient's family, five individuals were affected with atypical haemolytic uraemic syndrome (aHUS) but not the patient. Renal biopsies (n = 3) showed glomerular basement membrane thickening with double contours, endothelial swelling and deposits of C3 and C1q. Electron microscopy revealed mesangial and subendothelial electron-dense deposits. Complement mutations in membrane cofactor protein (Y155D) and C3 (R713W and G1094R) were detected in all affected family members. The patient also had transient autoantibodies to factor H. The findings suggest that aHUS and glomerulopathy resembling membranoproliferative glomerulonephritis may have a common molecular background.

Immune Complex-Type Deposits in the Fischer-344 to Lewis Rat Model of Renal Transplantation and a Subset of Human Transplant Glomerulopathy

Antibody-mediated rejection is a leading cause for renal transplant loss. Rodent models are useful to dissect pathomechanisms and to develop treatment strategies. Although used for decades as a model, glomerular histopathological findings of Fischer-344 kidneys transplanted into Lewis rats have never been comprehensively described. Kidneys from Fischer-344 rats were transplanted into Lewis rats as life-sustaining allografts without immunosuppression. Lewis isografts and normal Fischer-344 kidneys served as controls. Grafts were harvested at 9 days, 6 and 26 weeks. Histopathological examination included light microscopy, immunohistochemistry, and morphometry. Findings were compared with 51 human biopsies with transplant glomerulopathy. Most glomerular findings in rat allografts resembled human acute and chronic antibody-mediated rejection with glomerulitis, microthrombosis, microaneurysms, glomerular hypertrophy, podocyte loss, glomerular basement membrane splitting, and secondary focal and segmental glomerulosclerosis. In line with previous reports on nonendothelial antigens, glomerular immunoglobulin and C4d deposition was mostly nonendothelial. Only in 26-week allografts, we found mesangial and subendothelial immune complex-type electron-dense deposits. Similar deposits were found in 8 of 51 human biopsies with transplant glomerulopathy after rigorous exclusion of immune complexes of other cause, particularly recurrent glomerulonephritis and hepatitis C. Thus, our model closely reflects the glomerular changes of acute antibody-mediated rejection in humans and of a special subset of human transplant glomerulopathy. The significance of alloimmune immune complex-type deposits in human transplants deserves further investigation.