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Post-infectious glomerulonephritis (PIGN) is an immune complex mediated glomerular injury occurring because of an infection, most commonly with group A beta-hemolytic streptococcus in children. C3 glomerulopathy (C3G) is a distinct clinicopathological entity occurring secondary to dysregulation of alternate complement pathway encompassing both C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). While most patients with PIGN attain complete remission with normalized complement levels by 6-8 weeks after presentation, patients with C3G continue to have hypocomplementemia with high rates of progressive kidney disease. Here, we report a patient diagnosed with dense deposit disease after his initial presentation with PIGN three years prior. While current literature continues to explore the overlapping and distinguishing features of PIGN and C3G, including how underlying defects in the alternate complement pathway may commonly contribute to both diseases, this case further exemplifies the importance of recognizing the clinico-pathogenic features of PIGN and C3G in pediatric patients with glomerulonephritis., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Glutathione reductase-like metalloid reductase (GRLMR) is an enzyme that reduces selenodiglutathione (GS-Se-SG), forming zerovalent Se nanoparticles (SeNPs). Error-prone polymerase chain reaction was used to create a library of ∼10,000 GRLMR variants. The library was expressed in BL21 Escherichia coli in liquid culture with 50 mM of SeO 3 2- present, under the hypothesis that the enzyme variants with improved GS-Se-SG reduction kinetics would emerge. The selection resulted in a GRLMR variant with two mutations. One of the mutations (D-E) lacks an obvious functional role, whereas the other mutation is L-H within 5 Å of the enzyme active site. This mutation places a second H residue within 5 Å of an active site dicysteine. This GRLMR variant was characterized for NADPH-dependent reduction of GS-Se-SG, GSSG, SeO 3 2- , SeO 4 2- , GS-Te-SG, and TeO 3 2- . The evolved enzyme demonstrated enhanced reduction of SeO 3 2- and gained the ability to reduce SeO 4 2- . This variant is named selenium reductase (SeR) because of its emergent broad activity for a wide variety of Se substrates, whereas the parent enzyme was specific for GS-Se-SG. This study overall suggests that new biosynthetic routes are possible for inorganic nanomaterials using laboratory-directed evolution methods.

When a defined protein/peptide (or combinations thereof) control and define the synthesis of an inorganic nanoparticle, the result is a cloneable NanoParticle (cNP). This is because the protein sequence/structure/function is encoded in DNA, and therefore the physicochemical properties of the nanoparticle are also encoded in DNA. Thus the cloneable nanoparticle paradigm can be considered as an extension of the central dogma of molecular biology ( e.g. DNA → mRNA → protein → cNP); modifications to the DNA encoding a cNP can modify the resulting properties of the cNP. Inorganic ion oxidoreductases ( e.g. , mercuric reductase, tellurite reductase, etc. ) can select and reduce specific inorganic oxyanions and coordination complexes, creating zerovalent precipitates. Other proteins/peptides (often genetically concatenated to the parent oxidoreductase) serve as ligands, directing the size, shape, crystal structure and other properties of the nanoparticle. The DNA encoding a cNP can be recombinantly transferred into any organism. Ideally, this enables recombinant production of cNPs with the same defined physiochemical properties. Such cNPs are of interest for applications ranging from molecular imaging, bio-remediation, catalysis, and biomining. In this Feature Article we detail and define the cNP concept, and retrace the story of our creation of a cloneable Se NanoParticle (cSeNP). We also describe our more preliminary work that we expect to result in cloneable semiconductor quantum dots, cloneable Te nanoparticles, and other cNP formulations. We highlight the application of cNPs in cellular electron microscopy and compare this approach to other cloneable imaging contrast approaches.

Billions of COVID-19 vaccine doses have been administered to combat the ongoing global pandemic caused by severe acute respiratory syndrome coronavirus-2. While these vaccines are considered safe, with most adverse events being mild to moderate and transient, uncommon systemic side effects of the vaccines, including de novo or re-activation of various glomerular diseases have recently been observed. We report 6 patients who developed glomerular or acute tubulointerstitial disease shortly after receiving COVID-19 vaccinations. Five of these patients received mRNA vaccines (3 Moderna, 2 Pfizer-BioNTech) and 1 received adenovirus-26 vector vaccine (Johnson and Johnson/Janssen). Four of our patients developed de novo glomerulonephritis or acute tubulointerstitial nephritis (ATIN), while the other 2 had re-activation of prior glomerulonephritis. Two patients presented with acute kidney injury (AKI) characterized by severe ATIN. While both of them also had evidence of immune complex glomerular disease, ATIN was the dominant feature on the biopsies. Two other patients presented with high-grade proteinuria and AKI. Like the aforementioned patients, these patients had evidence of immune complex glomerular disease, but acute onset nephrotic syndrome was the leading clinical feature. Another patient presented with de novo myeloperoxidase-anti-neutrophil-cytoplasmic-antibody-associated pauci-immune crescentic glomerulonephritis. Yet another patient had re-activation of immunoglobulin-A glomerulonephritis that had been quiescent for several years prior to the vaccination. It is difficult to ascertain any causal relationship between COVID-19 vaccination and onset/recurrence of kidney diseases. However, vigilance about occurrence of such complications is imperative. Importantly, all our cases responded well to the immunosuppressive treatment.

BK virus is a polyomavirus with seroprevalence rates of 80% in adults. Infection is usually acquired during childhood, and the virus is benign or pathologic depending on immune status. The virus reactivates in immunodeficiency states, mostly among transplant (either kidney or bone marrow) recipients. There are approximately 15 000 renal transplants every year in the USA, of which 5-10% develop BK polyomavirus nephropathy; 50-80% of patients who develop nephropathy go on to develop graft failure. BK virus is associated with BK polyomavirus nephropathy, ureteral stenosis, late-onset hemorrhagic cystitis, bladder cancer and other nonlytic large T-expressing carcinomas. The renal spectrum begins with viruria and can end with graft failure. The clinical spectrum and outcomes vary among transplant patients. New noninvasive diagnostic methods, such as urinary polyomavirus Haufen detected by electron microscopy, are currently under study. Treatment is primarily directed at decreasing immunosuppression but may be associated with graft rejection. Repeat transplantation is encouraged as long as viral clearance in plasma prior to transplant is accomplished. There remain no definitive data regarding the utility of transplant nephrectomy., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

In 2013, the International Society of Heart and Lung Transplant (ISHLT) introduced the working classification for pathologic changes associated with antibody-mediated rejection (AMR) of the heart allograft, known as pathologic AMR (pAMR). With 2 components associated with AMR, histopathologic changes) and immunopathologic markers, the proposed classification also suggests the use of class II HLA as a marker of endothelial integrity. It is known that during allograft rejection, endothelial cells are activated, therefore, we hypothesized that endothelial class II HLA rather than a marker of mere endothelial presence, is a marker of endothelial activation and becomes upregulated in AMR. Eight hundred thirty-eight heart allograft biopsies, collected from January 2016 to September 2018 at a single institution from patients with a current or recent diagnosis of AMR, were evaluated for both histopathologic and immunopathologic changes of AMR. Biopsies were labeled with immunofluorescence with antibodies against C4d and for immunohistochemistry with antibodies against C3d, CD68, and class II HLA. ISHLT criteria were used to classify the biopsies, and for class II HLA, both the percentage and the stain intensity were evaluated. Biopsies (74.8%) from our cohort showed either histopathologic pAMR-1, immunopathologic pAMR-1, or combined histopathologic and immunopathologic pAMR-2 evidence of AMR. Expression of endothelial HLA class II was significantly correlated with the diagnosis of AMR by percentage area (P < .0001) and intensity of staining (P < .0001). The diagnosis of AMR significantly correlated with moderate (+2) and strong (+3) staining intensity for class II HLA as follows: histopathologic and immunopathologic pAMR-2 with odds ratio (OR) = 28.3 (P < .0001);histopathologic pAMR-1 alone with OR = 22.7 (P < .0001); and immunopathologic pAMR-1 alone with OR = 32.6 (P < .0001). Interestingly, our study also suggested that the inclusion of C4d focally positive cases also significantly correlates with the diagnosis of AMR (P < .003). We confirmed our hypothesis that in heart allograft biopsies, there is a spectrum of both percentage and intensity of HLA class II expression due to endothelial activation, and that class II HLA by immunohistochemistry is a marker significantly correlated with the diagnosis of AMR. In addition, the group of focally positive C4d biopsies (10%-50%) should be considered positive for the immunopathologic component of the 2013 ISHLT classification, as this group of biopsies also correlated with the diagnosis of AMR., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Over the last decade important research discoveries have revealed that most "idiopathic" cases are caused by autoantibodies to podocyte antigens including phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain containing 7A (THSD7A). In this review, we will discuss the histopathology of primary MN, recent revelations regarding pathogenesis, and ancillary tests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: C3 glomerulopathy (C3G) is defined by dominant glomerular deposition of C3 and minimal or no immunoglobulin, with two subtypes-dense deposit disease (DDD) and C3 glomerulonephritis (C3GN)-distinguished by features on electron microscopy (EM). Given that this rare disease has generally unfavorable yet highly variable outcomes, we sought out to review the histopathology, complement/genetic studies, and renal outcomes of pediatric patients with C3G at our institution., Methods: All native kidney biopsies performed in a single pediatric hospital over a 10-year period were reviewed for features of C3G. Of 589 biopsy reports, we identified 9 patients fulfilling the diagnostic criteria for C3G and retrospectively reviewed their clinical chart and renal biopsy findings., Results: We identified 4 patients with DDD, 4 with C3GN, and 1 indeterminate case, with features of both C3GN and DDD. Five patients were positive for one or more nephritic factors (C3NeF, C4NeF, C5NeF) with 1 patient additionally positive for complement factor H (CFH) autoantibody. Genetic testing done in 5 of the 9 patients failed to identify any causative mutations. Three patients showed progressive renal dysfunction over a mean follow-up period of 33 months., Conclusions: Complement and genetic studies are now routinely recommended for patients with a histopathological diagnosis of C3G. Careful interpretation of these studies and their prognostic and therapeutic implications in conjunction with biopsy findings is needed to further understand the pathophysiology of this rare disease in children.

Introduction: PCAR is a rare form of ACR that may compromise renal allografts. This review evaluates the outcomes of a protocol used to treat PCAR (Study group), and compares these outcomes with a matched cohort with ACR (Control group)., Methods: A retrospective analysis of 138 of pRTRs who underwent renal allograft biopsies between January 2008 and November 2016., Results: Seven biopsies revealed in situ hybridization of EBER-negative PCAR (5%). Three Study group pRTRs lost their grafts within 3 months after rejection (43%). None of the Control group pRTRs lost their graft during this period. At the time of rejection, eGFR was different between the Control and Study groups (27.0 ± 19.9 mL/min per m 2 vs 40.0 ± 10.6 mL/min/1.73 m 2 , respectively; P < 0.05). Among Study group pRTRs with functioning allografts (n = 4), treatment resulted in an increase in eGFR from nadir levels (27.0 ± 19.9 vs 55.6 ± 18.3 mL/min/1.73 m 2 , P < 0.05). In the Study group, complications included neutropenia, BK and EBV viremia, and infusion-related hypotension and hypertension., Summary: (a) Graft loss in Study group while remaining high (43%) was lower than that reported in the published pediatric literature. (b) Our protocol was associated with improvement in eGFR in all surviving pRTRs within the Study group. (c) No life-threatening complications or malignancy were reported during the observation period., (© 2019 Wiley Periodicals, Inc.)

Background: The 2013 Banff meeting updated the requirements for the diagnosis of acute/active antibody-mediated rejection (AAMR) in kidney allografts. There has been speculation that the changes lower the threshold for diagnosing AAMR, and may lead to possible unnecessary and expensive treatment., Methods: We compared the 2013 Banff classification for AAMR to the previous 2007 Banff to determine if there was an increase in the number of patients receiving a diagnosis of AAMR and if the diagnosis affected allograft survival and post-biopsy 3-month and 6-month creatinine and eGFR values., Results: A total of 212 renal allograft biopsies were compared to both 2007 and 2013 Banff classification requirements for AAMR. Ten patients (11 biopsies) met the 2007 criteria. An additional 15 patients (20 biopsies) met the 2013 criteria. These 2 groups showed no statistically significant demographic differences. By applying the 2013 Banff classification, we observed a 2.5-fold increase in the number of AAMR cases. One-year post-transplant allograft survival was higher in the 2013 group (.85 vs .55) and the 3-month and 6-month post-biopsy creatinine values were significantly lower for the 2013 group (1.6 ± .6 vs 3.3 ± 2.2, P value .01, and 1.7 ± .6 vs 3.4 ± 2.8, P value .03). The 3-month and 6-month eGFR values were higher in the 2013 group, although not statistically significant., Conclusions: These results suggest that use of Banff 2013 criteria in place of Banff 2007 may result in diagnosing milder and earlier cases of AAMR with the possibility of initiating earlier treatment and improving graft outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In adults, membranous nephropathy is the second most common cause of nephrotic syndrome. In contrast, minimal change disease and focal segmental glomerulosclerosis constitute the most common forms of nephrotic syndrome in children, while membranous nephropathy accounts for <5% of cases. In adults, causes of membranous nephropathy include autoantibodies directed against phospholipase A 2 receptor and thrombospondin type 1 containing 7A, various infections, environmental toxicities, autoimmune disorders, malignancies, and other secondary forms. The most common causes of secondary membranous nephropathy in children are infections, autoimmune diseases, and neoplasia. We discuss an unusual presentation of new-onset membranous nephropathy due to mercury toxicity in a 14-year-old male with reflux nephropathy. This case underscores the importance of a high index of suspicion for uncommon causes of nephrotic syndrome in pediatric patients with membranous nephropathy., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Denosumab and abiraterone were approved by the United States Food and Drug Administration in 2011 for the treatment of metastatic castration-resistant prostate cancer. Neither denosumab nor abiraterone is known to cause rhabdomyolysis., Case Presentation: A 76-year-old Caucasian man with metastatic prostate cancer presented with non-oliguric severe acute kidney injury (AKI) 3 weeks after receiving simultaneous therapy with denosumab and abiraterone. The patient had been on statin therapy for more than 1 year with no recent dose adjustments. His physical exam was unremarkable. Blood work on admission revealed hyperkalemia, mild metabolic acidosis, hypocalcemia, and elevated creatine kinase (CK) at 44,476 IU/L. Kidney biopsy confirmed the diagnosis of rhabdomyolysis-induced AKI. The patient responded well to intravenous isotonic fluids and discontinuation of denosumab, abiraterone, and rosuvastatin, with normalization of CK and recovery of kidney function., Conclusion: We report the first case of biopsy-proven rhabdomyolysis-induced AKI in a cancer patient acutely exposed to denosumab and abiraterone. Whether one of these drugs individually, or the combination, was the bona fide culprit of muscle breakdown is unknown. Nonetheless, our report is hypothesis-generating for further investigations on the effect of these drugs on muscle cells.

Renal medullary angiitis is a lesion involving the vasa recta of the medulla. The characteristic morphologic findings on renal biopsy include interstitial hemorrhage with associated polymorphonuclear leukocyte infiltration and karyorrhectic debris. A total of 18 cases have been described in three publications, all in the setting of antineutrophil cytoplasmic antibody (ANCA)-associated disease. We sought to detail the morphology and clinical significance of this lesion. A total of 38 cases of medullary angiitis were identified in our case files from January 2008 through August 2011. The clinical history was reviewed and pertinent information including patient age, gender, indication for biopsy, serum creatinine, and any positive serologic tests (ANCA) was collected for each biopsy. Cases with known and unknown ANCA status were reported separately. In total, 19 (63%) of 30 cases of medullary angiitis with known ANCA antibody status were ANCA positive, whereas 11 (37%) of 30 were determined to be secondary to other etiologies. The most common non-ANCA etiology of medullary angiitis was immunoglobulin A nephropathy (20%) followed by antibiotic treatment in the setting of infection. In ANCA-unknown cases, 4 (50%) of 8 had pauci-immune crescentic glomerulonephritis. No cases had renal cortex involvement. This is the largest study to date detailing the morphology of medullary angiitis and the first to show medullary angiitis outside the setting of ANCA-associated disease. It is an important lesion to recognize as it frequently suggests the presence of a systemic vasculitis and could be mistaken for interstitial nephritis., (Copyright © 2013 Elsevier Inc. All rights reserved.)