Arkana Advances: Recent Episodes
Arkana Laboratories
Arkana Advances is a research podcast, hosted by Dr. Rebecca May, discussing the work of Arkana physicians and scientists as they ask questions that lead to advancing the understanding of disease.
Over the past decade, there has been a dramatic increase in kidney biopsy inadequacy rate. Evaluation of biopsy adequacy by pathology is often not available. This study utilizes a smartphone camera to take a photograph of the biopsy at the bedside, which is then enlarged to allow for distinction between cortex and medulla. The physician performing the procedure, most often a radiologist, can then decide if additional samples are needed. In this study, there was a high agreement rate in the determination of adequacy between pathology (using a dissecting microscope) and radiology (using a smartphone). This method of determining specimen adequacy has the potential to decrease the biopsy inadequacy rate while simultaneously lowering cost and improving patient outcome.Read the paper:https://journals.lww.com/jasn/pages/articleviewer.aspx?year=2021&issue=12000&article=00012&type=Fulltext
Membranous glomerulopathy is an autoimmune disease-causing nephrotic syndrome in which there is subepithelial deposition of IgG and complements along the glomerular basement membrane. Membranous glomerulopathy is the second leading cause of nephrotic syndrome in adults. Following the description of the first membranous antigen PLA2R in 2009, there has been numerous antigens described and associations with different diseases. In addition to a discussion of the individual antigens, this review article covers a description of techniques for discovery of new antigens and how these techniques have changed over time.
NELL1 is a recently described antigen seen in membranous glomerulopathy, which has been associated with malignancy. A recent study linked Lipoic Acid supplementation with membranous glomerulopathy. In this letter to the editor, medication use was examined in 115 patients with NELL1 positive membranous glomerulopathy and 200 patients with membranous glomerulopathy of other types. In the NELL1 positive group, 15 patients had active Lipoic Acid use, while no Lipoic Acid supplementation was seen in the non-NELL1 membranous group. In addition to a malignancy workup in patients diagnosed with NELL1 positive membranous glomerulopathy, patients should also be asked about Lipoic Acid supplementation.
Read the paper: https://www.kidney-international.org/article/S0085-2538(21)01140-6/fulltext
A renal biopsy is an invasive procedure requiring sedation that is often necessary for appropriate patient treatment. A biopsy is "inadequate" when a complete diagnosis cannot be rendered, usually due to the lack of sufficient renal cortex within the biopsy. Over a 16 year period, a total of 123,372 native renal biopsies were received at Arkana Laboratories. The rate of inadequate kidney biopsies increased from approximately 2% in 2005 to 14% in 2020. In 2005, only 5% of biopsies were performed by radiology. This increased to 95% performed by radiology in 2018. The rate of inadequate biopsies increased over time for both radiology and nephrology but was much higher for radiology. This correlates with the diameter of needles used by radiology (18g/20g) vs nephrology (14g/16g). The rate of deep misses, where the biopsy is predominately medulla, is higher in radiology performed biopsies. We have many resources available at Arkana Labs if your institution is struggling with inadequate biopsies. If your renal biopsies are read at Arkana Labs, we can pull the miss rate for your hospital and also offer training programs incorporating different tools to assess adequacy in real-time.
Read the paper: Increasing Incidence of Inadequate Kidney Biopsy Samples Over Time: A 16-Year Retrospective Analysis From a Large National Renal Biopsy Laboratory
Approximately half of lupus patients have kidney disease, including membranous glomerulopathy. On renal biopsy, immunofluorescence shows granular capillary loop deposits, and holes are seen in the capillary loops on silver stain. Electron microscopy shows subepithelial immune complex deposits. It is important to determine an antigen in these cases, as it can be linked to patient prognosis. The most common antigen seen in membranous lupus nephritis is EXT1/2, followed by NCAM1. This study identified a new target antigen, TGFBR3, seen in approximately 6% of membranous lupus nephritis cases. TGFBR3 was also seen in a few patients with membranous glomerulopathy and other autoimmune diseases. Of 15 patients who were followed clinically, only 2 achieved clinical remission (average 11-month follow-up). Patients with TGFBR3 positive membranous glomerulopathy should undergo a workup for autoimmune disease.
Read the paper: https://kidney360.asnjournals.org/content/kidney360/2/8/1275.full.pdf?with-ds=yes
The association of rare autoimmune responses to vaccination is well known. This study investigates the effect of COVID-19 vaccination on the kidney. In a six-month period, 29 cases (including relapse of disease) were identified with temporal association to COVID-19 vaccination out of approximately 10,000 biopsies. The most common diagnoses were IgA Nephropathy (10 cases), minimal change disease (7 cases), and crescentic glomerulopathy with positive ANCA (6 cases). The overall frequency of these diseases was not increased compared to pre-pandemic levels. The true incidence and association with vaccination is not entirely clear in this period of mass vaccination. An NIH registry for glomerulonephritis post-COVID-19 vaccination has been created to further study this topic and is open to international patients. See the link below if you would like to register a patient.
Link to the registry (Glomerulonephritis post-COVID-19 vaccination): https://redcapsurvey.niddk.nih.gov/surveys/?s=LCDAMFD9JA
Read the paper: https://kidney360.asnjournals.org/content/kidney360/2/11/1770.full.pdf?with-ds=yes
Membranous nephropathy is a leading cause of nephrotic syndrome. On renal biopsy, immunofluorescence shows granular capillary loop deposits, and holes are seen in the capillary loops on silver stain. Electron microscopy shows subepithelial immune complex deposits. Membranous glomerulopathy can be seen in association with autoimmune diseases including lupus. The most common antigen seen in membranous lupus nephritis is EXT1/2. This study identified a new target antigen, NCAM1, which was present in 6.6% of membranous lupus nephritis cases. Few cases of NCAM1 membranous were seen in patients with non-lupus autoimmune disease. NCAM1 can also be detected in the serum of these patients. Approximately 40% of patients had neuropsychiatric disease, including seizures and cerebritis. Clinical outcomes for these patients are still unknown.
Read the paper: https://www.kidney-international.org/action/showPdf?pii=S0085-2538%2820%2931180-7
Watch the episode: https://youtu.be/ObMt9z8U0fY
Membranous nephropathy is a leading cause of nephrotic syndrome. On renal biopsy, immunofluorescence shows granular capillary loop deposits, and holes are seen in the capillary loops on silver stain. Electron microscopy shows subepithelial immune complex deposits. A majority of cases have autoantibodies against PLA2R and THSD7A. This study identified a new target antigen, NELL1, which was present in 1.7% of membranous cases. NELL1 can also be detected in the serum of these patients. Approximately 33% of patients with NELL1 have a known malignancy. Patients with successful treatment of the malignancy showed good responses to membranous treatment. Patients with NELL1 positive membranous nephropathy should receive age-appropriate cancer screening.
Read the paper: https://www.kidney-international.org/action/showPdf?pii=S0085-2538%2820%2930956-X
Watch the episode: https://www.youtube.com/watch?v=WdMk3gAo7mc&feature=youtu.be
Nephrocalcinosis is the finding of abundant calcium phosphate deposits within the tubulointerstitium of the kidney. This is a case report of a renal biopsy from an 11 month old male with hypercalcemia and developmental delay, who was found to have nephrocalcinosis. It is a rare diagnosis in infants, and should prompt a genetic workup. Genetic workup revealed a CYP24A1 mutation, which results in a truncated protein. This is a novel mutation in this gene. CYP24A1 is involved in Vitamin D metabolism. It is important to publish these mutations so geneticists can create databases of pathogenic mutations, and to provide prognostic information to patients.
Read the Paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551537/pdf/main.pdf
Watch the episode: https://www.youtube.com/watch?v=lxQrEIbbb0E
In patients with chronic kidney disease, toxins normally excreted by the kidney continue to circulate, leading to increased kidney damage. The gut microbiome likely plays a role in this damage and contributes to systemic inflammation. Supplementation with dietary fiber (resistant starch) may prevent this kidney damage. This study uses a mouse model of chronic kidney disease and showed that mice fed resistant starch had significantly less kidney fibrosis. A diet including resistant starch altered the gut microbiome, with changes detected in proteins involved in gut permeability and the inflammatory response. This dietary change may improve outcomes in patients living with chronic kidney disease.
Read the paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547583/pdf/PHY2-8-e14610.pdf
Watch the episode: https://www.youtube.com/watch?v=QGY_mcILcIQ
This discussion focuses on a review article of crystals seen in renal biopsies. Crystalline nephropathies are often associated with systemic conditions. We discuss calcium-based crystals, dysproteinemia-related (such as light chain), crystal storing histiocytosis, crystalglobulin/cryocrystalglobulin, metabolic disorders, and drug-associated crystals. We review the appearance of the crystals, their etiology, and the associated prognosis for the patient. This is an excellent synopsis of the most common renal crystals for both trainees and practicing renal pathologists.
Read the Paper: A diagnostician's field guide to crystalline nephropathies
Watch the Video: https://www.youtube.com/watch?v=KpDPpzHLiZI
Dr. May discusses a review article with Dr. Dvanajsack that focuses on renal intratubular casts in Episode 5 of Arkana Advances.
Both benign casts as well as six types of pathologic casts are addressed (light chain casts, myoglobin/hemoglobin casts, red blood cell casts, neutrophil casts, and bile casts). The pair review the appearance of these casts, their etiology, and the associated prognosis for the patient. This is an excellent synopsis of the most common renal casts for both trainees and practicing renal pathologists.
Read the paper: A Practical Approach To The Pathology Of Renal Intratubular Casts
Watch the episode: https://youtu.be/EOYSCkSjBYg
In Episode 4 of Arkana Advances, Dr. May interviews Dr. Cassol over her recent publication discussing viral-like inclusions in COVID-19 negative renal biopsies detected by electron microscopy.
Early in the COVID-19 pandemic in the United States, few publications from different organ systems claimed to have found COVID-19 viral particles, including in the kidney. Viral particles are known to be of varying sizes, making proper identification even more difficult. To see whether these viral particles are specific for COVID-19 infection, both pre-COVID and COVID-era biopsies were examined. Viral-like inclusions were seen in all cases studied. These mimickers of COVID virions are hypothesized to be clathrin-coated endocytic vesicles, microvesicular bodies, or small organelles. COVID-19 ISH was performed in a few cases of patients with active COVID, and no viral RNA was detected. The CDC has outlined principles of identification of viruses on electron microscopy, including the proper protocols for preparation of the samples.
Read the Paper: Viral-like Inclusions in COVID-19 Negative Renal Biopsies by Electron Microscopy
Watch the Episode: https://youtu.be/45-ZHL1gVSc
Dr. May and Dr. Larsen discuss Covid-19 and its effect on collapsing glomerulopathy and APOL1 in Episode 3 of Arkana Advances.
Collapsing glomerulopathy is a variant of focal segmental glomerulosclerosis (FSGS) in which there is capillary loop collapse and epithelial cell hyperplasia and hypertrophy. There is rapid progression to end-stage renal disease. Early in the COVID-19 pandemic in the United States, these publications demonstrated for the first time that collapsing glomerulopathy is seen in African American patients with COVID-19 infection, and is associated with an APOL1 High-Risk genotype. Direct viral infection of the kidney parenchyma was not identified. NanoString analysis showed activation of genes involved in tubular injury, as well as chemokines/cytokines and immunoglobulin. These findings are similar to that seen in HIV-associated nephropathy, wherein patients with an APOL1 high-risk genotype, HIV serves as a "second hit" to initiate collapsing glomerulopathy. Multiple publications have since confirmed, on a larger scale, the association of COVID-19 and collapsing glomerulopathy.
Read the papers: Collapsing Glomerulopathy in a patient with COVID-19 and AKI and Collapsing Glomerulopathy Associated with COVID-19 and APOL1 High-Risk Genotype
Watch the video: https://youtu.be/mWyAepgQDCI
Anti-brush border antibody disease is a rare autoimmune disease. Auto-antibodies are targeted against LRP2/Megalin, which is present on the apical brush border of the proximal tubule epithelial cells and is an endocytic receptor for many substances. This disease is typically seen in elderly patients who present with acute kidney injury. On renal biopsy, light microscopy shows acute tubular injury. Granular tubular basement membrane, as well as apical brush border staining for IgG, is seen on immunofluorescence. IgG and LRP2 colocalize along the tubular basement membrane. In this case report, a 55-year-old male with a recent diagnosis of Lupus underwent kidney biopsy for acute kidney injury and proteinuria. He was found to have focal lupus nephritis, class III, as well as anti-brush border antibody disease. Serology for LRP2 antibodies was positive. This is the first case report of this disease in a patient with lupus and is unusual in that the patient is non-elderly. This may be an under-recognized disease, especially in patients with other autoimmune diseases.
Read the publication: Anti–Brush Border Antibody Disease (Anti-LRP2 Nephropathy) Associated With Lupus Nephritis
Membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) is a rare condition in which subepithelial deposits are present on electron microscopy (compatible with membranous glomerulopathy), but routine immunofluorescence is exclusively positive for C3. When a different processing technique is used and immunofluorescence is performed on the paraffin-embedded tissue, staining is "unmasked" revealing deposits that stain with IgG1, C3, and kappa. These patients are more often younger women and have a vague autoimmune phenomenon, such as a weakly positive ANA. To identify an antigen for membranous-like glomerulopathy with masked IgG kappa deposits, mass spectrometry was performed on laser captured glomeruli. There was a high expression of serum amyloid P (SAP) as compared to non-MGMID cases. SAP co-localized with IgG within deposits by confocal microscopy in MGMID cases. On a larger cohort, SAP was positive in membranous-like glomerulopathy with masked IgG kappa deposits cases and few membranous cases that did not mask, but were IgG1 kappa restricted, suggesting that not all cases are masked on immunofluorescence. Staining for SAP provides a convenient way to test for MGMID in clinical practice.
Read the paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869973/pdf/nihms-1587026.pdf