Search

Previous studies have demonstrated residual complement-mediated deposits in repeat kidney biopsies of C3 glomerulopathies (C3G) (dense deposit disease (DDD) and C3 glomerulonephritis) following eculizumab treatment, despite some clinical improvement. With residual complement deposition, it is difficult to determine whether there is a reduced complement-mediated endothelial cell injury. We validated that myeloperoxidase (MPO) immunohistochemical staining identified glomerular endothelial cell injury in crescentic glomerulonephritis and C3G. We report that MPO staining in the glomerular endothelium of the post-treatment kidney biopsy was significantly reduced after 3 years of eculizumab treatment and clinical improvement in a 5-year-old boy with initial DDD and secondary crescent formation. We find that immunostaining for MPO is a useful method to compare glomerular endothelial injury in C3G following eculizumab treatment. This finding also supports the notion that eculizumab, a C5 blocker, may not mainly block C3 deposits in the glomeruli but significantly blocks final activation of the complement cascade, thus reducing glomerular endothelial cell injury.

The overlap syndromes of anti-neutrophil cytoplasmic antibodies (ANCA)-associated crescentic glomerulonephritis (AACGN) and variants of immune complex medicated glomerulopathy (ICMGN) have been reported. But very few have compared AACGN alone with the overlap syndromes (AACGN plus ICMGN). The aim of this retrospective study was to make that comparison, following serum creatinine (sCr) to determine whether the two groups (AACGN-only group versus overlap group) would behave differently over time. We identified 14 cases with dual diagnoses of AACGN and various ICMGN in the overlap group. Data were collected and compared with 15 randomly selected AACGN-only cases over the similar period of time. The overlap syndrome represented 0.35% of our overall biopsies (14/4049). All 14 patients were ANCA positive and had crescentic formation. The percentage of crescents in the biopsies ranged from 10 to 78%. ICMGN included the following: membranoproliferative glomerulonephritis, post-infectious glomerulonephritis, membranous glomerulopathies, idiopathic mesangial proliferative glomerulonephritis, lupus nephritis, and IgA nephropathy. With the exception one biopsy revealing lupus nephritis class III, most of the ICMGN were mild. When compared to the AACGN-only group, there were no significant differences in clinical and histologic indices including age, percent of crescents, and sCr (on biopsy days, and over the follow-up periods), although the numbers of follow-up cases were limited over time. Our findings suggest that AACGN was the dominant disease process in the majority of overlap syndromes between AACGN and ICMGN, similar to the clinical processes of AACGN-only disease, therefore, the AACGN in overlap syndrome cases should be the main target for clinical management.

Collapsing glomerulopathy (CGN) secondary to HIV or COVID-19 infection mainly occurs in patients of African American descent due to APOL-1 gene mutations, but CGN is occasionally reported in white patients. CGNs are rarely reported in renal transplant biopsies and their association with idiopathic focal segmental glomerulosclerosis (FSGS) is unclear.Patient #1 was a 48-year-old Caucasian white man who had a renal transplant 8 years ago and was recently diagnosed with COVID-19 infection. Two weeks post infection, his serum creatinine (SCr) increased to 2.01 mg/dL from a baseline of 1.40 mg/dL, and he developed concomitant nephrotic range proteinuria. The first renal transplant biopsy showed FSGS. Four weeks later, his sCr level increased to 2.65 mg/dL with worsening proteinuria, and a second renal transplant biopsy revealed CGN. Patient #2 was a 32-year-old African American man whose native renal biopsy revealed primary FSGS. He received a renal transplant with initial post-transplant sCr level at 1.17 mg/dL. Four months later, his sCr and protein-to-creatinine ratio began to rise. Sequential biopsies revealed that the patient had developed recurrent FSGS, which progressed to show features of CGN. The CGN was further confirmed in his transplant kidney graft at autopsy later.This is the first case report of CGN in a white renal recipient with COVID-19 infection. The pathologic presentations of FSGS progressing to collapsing FSGS in our 2 renal transplant recipients suggest that FSGS and GGN may share a common pathophysiologic mechanism of podocytopathy.

In idiopathic (primary) membranous glomerulopathy (MGN), there is a phenomenon of subepithelial deposits (stages 1 and 2) transitioned to intramembranous deposits, with lucent resolving features (stages 3 and 4). This phenomenon has not been described in other types of immune complex mediated glomerulonephritis with either subendothelial or mesangial deposits. The goal of this study was to evaluate what unique immunostaining pattern could occur in primary MGNs with intramembranous resolving features. PLA2R and IgG4 immunostains were performed in 50 primary MGNs, and 39 secondary MGNs after the clinical history was reviewed. Primary MGNs with resolving features were further evaluated in detail. A total of 84% (42/50) of primary MGN cases had diffuse positive immunostaining for IgG4 in the glomeruli, and most of them were also positive for PLA2R staining. Eight of the remaining primary MGN cases (8/50) with positive PLA2R but negative IgG4 staining in the glomeruli had diffuse resolving features as observed by electron microscopy. All secondary MGNs were stained negatively for both IgG4 and PLA2R except for one case with positive IgG4 staining but negative staining for PLA2R. Our data indicate that IgG4 staining on paraffin tissue is a very reliable screening tool to confirm the presence of primary MGN. Primary MGN with PLA2R+/IgG4- stains were seen in those with intramembranous resolving features. This finding is consistent with the known weak-binding capacity of IgG4 to the glomerular basement membranes. The transitional phenomenon from PLA2R+/IgG4+ subepithelial deposits to PLA2R+/IgG4- intramembranous resolving deposits in primary MGN implies that there may be a continuous metabolic activity from podocyte to glomerular basement membrane.

Vascular endothelial growth factor (VEGF) antagonists have been used for treating metastatic neoplasms. It has also been known that one of its side effects is to cause proteinuria and renal failure in the setting of thrombotic microangiopathy (TMA). The underlying mechanism is likely due to the inhibition of VEGF production in podocytes, resulting in diffuse fusion of foot processes and impaired glomerular endothelial fenestrations, and leading to massive proteinuria and subsequent glomerular endothelium injury. Intravitreal injection of VEGF antagonists (IIVA) has been also used to treat macular degeneration and diabetic retinal neo-vascular proliferation. The majority of patients tolerate the treatment well. However, IIVA can lead to renal dysfunction including proteinuria and gradual renal failure as a rare side effect. The goal of this study was to report two cases related to the nephrotoxicity of IIVA and review the literature associated with this topic.The first diabetic patient had elevated serum creatinine at 3.25 mg/dl and proteinuria/creatinine ratio at 6.1 after 48-month treatment of IIVA. The first renal biopsy revealed thrombotic microangiopathy that was correlated with his increased serum creatinine and nephrotic range of proteinuria. The second diabetic patient had increased serum creatinine up to 1.89 mg/dl but low proteinuria. The second biopsy showed acute tubular necrosis that was correlated with his elevated serum creatinine.Intravitreal injection of VEGF antagonist can be associated with thrombotic microangiopathy and acute tubular necrosis, leading to renal dysfunction.

Previous studies have demonstrated residual complement-mediated deposits in repeat kidney biopsies of C3 glomerulopathies (C3G) (dense deposit disease (DDD) and C3 glomerulonephritis) following eculizumab treatment, despite some clinical improvement. With residual complement deposition, it is difficult to determine whether there is a reduced complement-mediated endothelial cell injury. We validated that myeloperoxidase (MPO) immunohistochemical staining identified glomerular endothelial cell injury in crescentic glomerulonephritis and C3G.We report that MPO staining in the glomerular endothelium of the post-treatment kidney biopsy was significantly reduced after 3 years of eculizumab treatment and clinical improvement in a 5-year-old boy with initial DDD and secondary crescent formation.We find that immunostaining for MPO is a useful method to compare glomerular endothelial injury in C3G following eculizumab treatment. This finding also supports the notion that eculizumab, a C5 blocker, may not mainly block C3 deposits in the glomeruli but significantly blocks final activation of the complement cascade, thus reducing glomerular endothelial cell injury.

Kidney injury molecule-1 (KIM-1) staining has been shown to be very useful in identifying acute proximal tubular injury, but its sensitivity, specificity and predicting values for the recovery of renal function after injury in renal biopsies have not been well established. In the first study, we randomly selected 184 renal biopsies from a wide age range of patients (children to elderly) with various renal diseases. KIM-1 staining scores were significantly correlated with serum creatinine (sCr) levels (P

Introduction/Objective IgG4 related disease, a systemic autoimmune inflammatory disorders, can be identified by high% of IgG4 positive plasma cells, thus IgG4 staining in paraffin embedded tissue is widely available in the most of pathology labs. IgG4 staining has been found useful to identify primary MGN (PLA2R and/or THSD7A positive) by others and us. This study was to scrutinize the findings of primary vs secondary MGN needed for IgG4 staining as a screening tool in our renal pathology practice over pasts 5 years Methods/Case Report IgG4 staining in paraffin embedded tissue was performed in 45 primary MGN and 43 secondary MGN after the clinical history was reviewed and a possibility of primary MGN cannot be excluded. In addition, both groups of cases were also stained for PLA2R. Detail correlation with clinical history was analyzed. Results (if a Case Study enter NA) Totally 82 % (37/45) of primary MGN was found diffuse positive for IgG4 staining at 2+ intensity in the glomeruli. Seven out of eight remaining primary MGN cases with either negative or weak IgG4 stained MGN were found to have diffuse resolving features by electron microscopy but there was still positive PLA2R staining in the glomeruli. All secondary MGN were stained negatively for both IgG4 and PLA2R and we found that etiologies of the secondary MGN included membranous lupus nephritis, infection, GVHD, or variants of cancers. Conclusion Our data indicate that IgG4 staining along (without IgG1-3 staining) is a reliable screening tool to confirm the majority of primary MGN vs secondary MGN in paraffin embedded tissue. As both PLA2R+ and THSD7A+ primary MGN are both IgG4 related, the IgG4 staining may potentially represent a wider range of scope in identifying primary MGN. In addition, negative/weak IgG4 staining in PLA2R-positive MGN most likely represents a primary MGN with resolving features.

Electron microscopy (EM) has been mainly used for identifying ultrastructural abnormalities such as fusion of foot processes and immune complex deposits in glomeruli. However, electron microscopic findings in renal tubules can provide either diagnostic evidence (unique finding) or supportive evidence (additional finding) for final diagnosis. Here we present multiple situations that EM can be used for drawing conclusions of various drug-associated nephrotoxicity. Multiple cases with drug-induced nephrotoxicity are reviewed, including clinical history, EM findings, and serum creatinine (sCr) levels, prior to renal biopsy and during follow-up. Two cases with nephrotoxicity by aminoglycoside antibiotics showed acute tubular injury with EM findings of myeloid bodies, characterized by laminated dense materials in lysosomes in both proximal and distal tubular epithelium (diagnostic evidence). Five cases of vancomycin associated nephrotoxicity presented with acute tubular injury and vancomycin casts in distal tubules, characterized by central laminated casts in the lumina of distal tubules (supportive evidence). Vedolizumab, a humanized monoclonal antibody used in treating Crohn's disease, can cause T-cell dominant acute interstitial nephritis, with EM revealing lymphocytic infiltration into tubules as tubulitis (supportive evidence). Four of Seven cases (5/8) cases had renal functional recovery upon follow-up check for sCr. EM findings of characteristic changes in renal tubules can be particularly useful as either diagnostic or supportive evidence, in correlation with clinical history and etiologies of nephrotoxicity. Therefore, EM should not only focus on glomerular changes, but renal tubular changes as well.

The overlap syndromes of anti-neutrophil cytoplasmic antibodies (ANCA)-associated crescentic glomerulonephritis (AACGN) and variants of immune complex medicated glomerulopathy (ICMGN) have been reported. But very few have compared AACGN alone with the overlap syndromes (AACGN plus ICMGN). The aim of this retrospective study was to make that comparison, following serum creatinine (sCr) to determine whether the two groups (AACGN-only group versus overlap group) would behave differently over time. We identified 14 cases with dual diagnoses of AACGN and various ICMGN in the overlap group. Data were collected and compared with 15 randomly selected AACGN-only cases over the similar period of time. The overlap syndrome represented 0.35% of our overall biopsies (14/4049). All 14 patients were ANCA positive and had crescentic formation. The percentage of crescents in the biopsies ranged from 10 to 78%. ICMGN included the following: membranoproliferative glomerulonephritis, post-infectious glomerulonephritis, membranous glomerulopathies, idiopathic mesangial proliferative glomerulonephritis, lupus nephritis, and IgA nephropathy. With the exception one biopsy revealing lupus nephritis class III, most of the ICMGN were mild. When compared to the AACGN-only group, there were no significant differences in clinical and histologic indices including age, percent of crescents, and sCr (on biopsy days, and over the follow-up periods), although the numbers of follow-up cases were limited over time. Our findings suggest that AACGN was the dominant disease process in the majority of overlap syndromes between AACGN and ICMGN, similar to the clinical processes of AACGN-only disease, therefore, the AACGN in overlap syndrome cases should be the main target for clinical management.

Monoclonal gammopathy of renal significance (MGRS) is a state of circulating monoclonal immunoglobulin (Ig) and light chains that cause kidney injury without definite evidence of multiple myeloma (MM). Although chemotherapy is used to treat many variants of MGRS and has been recently recommended, relatively limited clinical validation studies are available. A few transgenic models of MM reveal renal deposition of monoclonal Ig and light chains. We have demonstrated that the XBP1s-transgenic mouse model from early plasma cell dyscrasia to MM reveals monoclonal IgG/kappa deposition at the subendothelial spaces of the glomeruli, mimicking proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Inhibition of a key immune-modulator, gp96/grp94, genetically or pharmacologically results in a significant reduction of plasma cells within the bone marrow and reduced renal deposition of monoclonal IgG and kappa light chain. This article will review the emerging role of

We report the case of an 8-month-old female infant presenting with bilateral, diffusely enlarged kidneys. A diagnosis of bilateral, universal nephroblastomatosis was made on tissue biopsies from both kidneys after correlation with the radiological findings. As far as we know, this is the oldest patient reported with this diagnosis in the English literature (they are usually younger than 4 months). The patient was treated with chemotherapy with very good response and almost 1 year later she is showing no signs of recurrence of her disease.

A total of 42 patients, who were diagnosed to have primary Immunoglobulin A nephropathy (IgAN) at the King Abdul Aziz University Hospital and King Faisal Hospital, Jeddah over the last seven years, were studied. The objective was to analyze their clinical and pathological features and to classify them according to Hass Classification by using light, immunofluorescence and electron microscopy. Majority of the study cases were males in the second, third and fourth decades of life. Hematuria was the most common clinical complaint followed by proteinuria. There were varying degrees of mesangial proliferation. Majority of the cases presented with class-2 followed by class-3. Immunofluorescence demonstrated diffuse granular deposition of IgA in the glomerular mesangium in majority of the cases. Ultrastructural analysis showed electron dense deposits within the matrix of the mesangium and paramesangium in majority of the cases. Sub-endothelial deposits and mesangial interposition were demonstrated in few cases. Extensive effacement with fusion of the visceral epithelial foot processes was detected in only few patients while focal effacement was demonstrated in many cases. Irregularities of the glomerular basement membrane were seen in some cases. We conclude that IgA nephropathy is an immune-complex glomerular disease, which occurs at all ages and with higher frequency in males and presents mostly with hematuria and proteinuria. Public health awareness is seriously needed to perform the investigations at an early stage.

We report a 36-year-old woman, presented with cervical lymphadenopathy and low-grade fever. Two fine needle aspiration cytology and one excisional biopsy were performed in the referral hospital, all showed granulomatous lesions without necrosis. A tentative diagnosis of tuberculosis was made, and she started on antituberculous treatment. However, there was no clinical improvement. She presented to our institution one year after the initial diagnosis, and a new biopsy from the cervical lymph node revealed effacement of the whole node by marked non-necrotizing granulomatous reaction. However, there were scattered large cells with few classic Reed-Sternberg cells between the granulomas. Immunohistochemistry reveals strong reaction of CD15 and CD30, and negative staining for CD45RB, CD45RO, and CD20. These findings confirmed the diagnosis of Hodgkin's lymphoma with remarkable granulomatous reaction that almost masked the malignant component. She was treated with chemotherapy, and she showed an excellent response.