An International Survey of Genitourinary and Renal Pathologists Regarding Evaluation of the Non-Neoplastic Parenchyma in Kidney Cancer Specimens.

Increasing survivorship in kidney cancer patients has shifted treatment strategies to optimize renal function preservation. In 2010, the College of American Pathologists (CAP) updated their synoptic reporting guidelines for tumor nephrectomies to require evaluation of the nonneoplastic kidney parenchyma. We conducted this study to understand current practice behaviors regarding the evaluation of the nonneoplastic kidney parenchyma in tumor nephrectomy specimens. We emailed a 14-item multiple-choice survey to members of the Renal Pathology Society and Genitourinary Pathology Society. We also emailed a 12-item survey to program and associate program directors of American pathology residencies to assess the current state of renal pathology education. Ninety-eight genitourinary and 104 renal pathologists responded to the survey on the nonneoplastic kidney parenchyma. Ninety-five percent of respondents who examine tumor nephrectomies reported evaluating the nonneoplastic kidney parenchyma. Seventy-five percent of genitourinary pathologists and 67% of renal pathologists use synoptic reporting, and 81% use the CAP protocol. Thirty-nine percent of respondents report always contacting the clinician when they find evidence of medical renal disease. Forty-two program leaders responded to our renal pathology education survey, and 64% of them have a mandatory renal pathology rotation that on average lasts about 2 to 4 weeks. The majority of pathologists examine the nonneoplastic kidney parenchyma of tumor nephrectomies and frequently report incidences of new medical renal disease directly to clinicians, but there remains room for improvement and educational gaps during residency training. Further efforts to standardize both this evaluation and renal pathology education will improve patient care.

Prospective observational study to validate a next-generation sequencing blood RNA signature to predict early kidney transplant rejection.

The objective of this study was to validate the performance of Tutivia, a peripheral blood gene expression signature, in predicting early acute rejection (AR) post-kidney transplant. Recipients of living or deceased donor kidney transplants were enrolled in a nonrandomized, prospective, global, and observational study (NCT04727788). The main outcome was validation of the area under the curve (AUC) of Tutivia vs serum creatinine at biopsy alone, or Tutivia + serum creatinine at biopsy. Of the 151 kidney transplant recipients, the mean cohort age was 53 years old, and 64% were male. There were 71% (107/151) surveillance/protocol biopsies and 29% (44/151) for-cause biopsies, with a 31% (47/151) overall rejection rate. Tutivia (AUC 0.69 [95% CI: 0.59-0.77]) and AUC of Tutivia + creatinine at biopsy (0.68 [95% CI: 0.59-0.77]) were greater than the AUC of creatinine at biopsy alone (0.51.4 [95% CI: 0.43-0.60]). Applying a model cut-off of 50 (scale 0-100) generated a high- and low-risk category for AR with a negative predictive value of 0.79 (95% CI: 0.71-0.86), a positive predictive value of 0.60 (95% CI: 0.45-0.74), and an odds ratio of 5.74 (95% CI: 2.63-12.54). Tutivia represents a validated noninvasive approach for clinicians to accurately predict early AR, beyond the current standard of care.

Specific in situ inflammatory states associate with progression to renal failure in lupus nephritis.

BACKGROUNDIn human lupus nephritis (LN), tubulointerstitial inflammation (TII) on biopsy predicts progression to end-stage renal disease (ESRD). However, only about half of patients with moderate-to-severe TII develop ESRD. We hypothesized that this heterogeneity in outcome reflects different underlying inflammatory states. Therefore, we interrogated renal biopsies from LN longitudinal and cross-sectional cohorts.METHODSData were acquired using conventional and highly multiplexed confocal microscopy. To accurately segment cells across whole biopsies, and to understand their spatial relationships, we developed computational pipelines by training and implementing several deep-learning models and other computer vision techniques.RESULTSHigh B cell densities were associated with protection from ESRD. In contrast, high densities of CD8+, γδ, and other CD4-CD8- T cells were associated with both acute renal failure and progression to ESRD. B cells were often organized into large periglomerular neighborhoods with Tfh cells, while CD4- T cells formed small neighborhoods in the tubulointerstitium, with frequency that predicted progression to ESRD.CONCLUSIONThese data reveal that specific in situ inflammatory states are associated with refractory and progressive renal disease.FUNDINGThis study was funded by the NIH Autoimmunity Centers of Excellence (AI082724), Department of Defense (LRI180083), Alliance for Lupus Research, and NIH awards (S10-OD025081, S10-RR021039, and P30-CA14599).

Association of Congenital and Acquired Cardiovascular Conditions With COVID-19 Severity Among Pediatric Patients in the US.

Importance: Identifying the associations between severe COVID-19 and individual cardiovascular conditions in pediatric patients may inform treatment. Objective: To assess the association between previous or preexisting cardiovascular conditions and severity of COVID-19 in pediatric patients. Design, Setting, and Participants: This retrospective cohort study used data from a large, multicenter, electronic health records database in the US. The cohort included patients aged 2 months to 17 years with a laboratory-confirmed diagnosis of COVID-19 or a diagnosis code indicating infection or exposure to SARS-CoV-2 at 85 health systems between March 1, 2020, and January 31, 2021. Exposures: Diagnoses for 26 cardiovascular conditions between January 1, 2015, and December 31, 2019 (before infection with SARS-CoV-2). Main Outcomes and Measures: The main outcome was severe COVID-19, defined as need for supplemental oxygen or in-hospital death. Mixed-effects, random intercept logistic regression modeling assessed the significance and magnitude of associations between 26 cardiovascular conditions and COVID-19 severity. Multiple comparison adjustment was performed using the Benjamini-Hochberg false discovery rate procedure. Results: The study comprised 171 416 pediatric patients; the median age was 8 years (IQR, 2-14 years), and 50.28% were male. Of these patients, 17 065 (9.96%) had severe COVID-19. The random intercept model showed that the following cardiovascular conditions were associated with severe COVID-19: cardiac arrest (odds ratio [OR], 9.92; 95% CI, 6.93-14.20), cardiogenic shock (OR, 3.07; 95% CI, 1.90-4.96), heart surgery (OR, 3.04; 95% CI, 2.26-4.08), cardiopulmonary disease (OR, 1.91; 95% CI, 1.56-2.34), heart failure (OR, 1.82; 95% CI, 1.46-2.26), hypotension (OR, 1.57; 95% CI, 1.38-1.79), nontraumatic cerebral hemorrhage (OR, 1.54; 95% CI, 1.24-1.91), pericarditis (OR, 1.50; 95% CI, 1.17-1.94), simple biventricular defects (OR, 1.45; 95% CI, 1.29-1.62), venous embolism and thrombosis (OR, 1.39; 95% CI, 1.11-1.73), other hypertensive disorders (OR, 1.34; 95% CI, 1.09-1.63), complex biventricular defects (OR, 1.33; 95% CI, 1.14-1.54), and essential primary hypertension (OR, 1.22; 95% CI, 1.08-1.38). Furthermore, 194 of 258 patients (75.19%) with a history of cardiac arrest were younger than 12 years. Conclusions and Relevance: The findings suggest that some previous or preexisting cardiovascular conditions are associated with increased severity of COVID-19 among pediatric patients in the US and that morbidity may be increased among individuals children younger than 12 years with previous cardiac arrest.

2',3',4'-Trihydroxychalcone changes estrogen receptor α regulation of genes and breast cancer cell proliferation by a reprogramming mechanism.

BACKGROUND: Menopausal hormone therapy (MHT) is recommended for only five years to treat vasomotor symptoms and vulvovaginal atrophy because of safety concerns with long-term treatment. We investigated the ability of 2',3',4'-trihydroxychalcone (2',3',4'-THC) to modulate estrogen receptor (ER)-mediated responses in order to find drug candidates that could potentially prevent the adverse effects of long-term MHT treatment. METHODS: Transfection assays, real time-polymerase chain reaction, and microarrays were used to evaluate the effects of 2',3',4'-THC on gene regulation. Radioligand binding studies were used to determine if 2',3',4'-THC binds to ERα. Cell proliferation was examined in MCF-7 breast cancer cells by using growth curves and flow cytometry. Western blots were used to determine if 2',3',4'-THC alters the E2 activation of the MAPK pathway and degradation of ERα. Chromatin immunoprecipitation was used to measure ERα binding to genes. RESULTS: The 2',3',4'-THC/E2 combination produced a synergistic activation with ERα on reporter and endogenous genes in human U2OS osteosarcoma cells. Microarrays identified 824 genes that we termed reprogrammed genes because they were not regulated in U2OS-ERα cells unless they were treated with 2',3',4'-THC and E2 at the same time. 2',3',4'-THC blocked the proliferation of MCF-7 cells by preventing the E2-induced activation of MAPK and c-MYC transcription. The antiproliferative mechanism of 2',3',4'-THC differs from selective estrogen receptor modulators (SERMs) because 2',3',4'-THC did not bind to the E2 binding site in ERα like SERMs. CONCLUSION: Our study suggests that 2',3',4'-THC may represent a new class of ERα modulators that do not act as a direct agonists or antagonists. We consider 2',3',4'-THC to be a reprogramming compound, since it alters the activity of ERα on gene regulation and cell proliferation without competing with E2 for binding to ERα. The addition of a reprogramming drug to estrogens in MHT may offer a new strategy to overcome the adverse proliferative effects of estrogen in MHT by reprogramming ERα as opposed to an antagonist mechanism that involves blocking the binding of estrogen to ERα.

Large Multinucleated Variant Endothelial Cells in Allograft Kidney Microvasculature: A Biopsy Series.

There are few published studies examining cytomorphologic alterations in endothelial cells in human tissue. One fascinating but largely unexplored endothelial morphologic variant is large multinucleated variant endothelial cells (MVECs). To our knowledge, there are no published reports of MVECs identified in the kidney. Here, we present a case series of 4 kidney biopsies from allograft kidneys whose microvasculature contained MVECs. Electron microscopy confirmed the endothelial identity in all cases. A broad immunohistochemical panel used in 1 case was also confirmatory of an endothelial cell origin. All cases occurred in the setting of chronic, active, antibody-mediated rejection, and alternative etiologies, such as viral infections, were excluded. Two patients were positive for concurrent donor-specific antibodies, and 3 of the 4 cases occurred in second kidney allografts. We speculate that MVECs are a rare or often overlooked finding often confused for megakaryocytes and may be associated with chronic endothelial cell injury in the setting of chronic antibody-mediated rejection.

Macrophage Depletion Reduces Disease Pathology in Factor H-Dependent Immune Complex-Mediated Glomerulonephritis.

Complement factor H (FH) is a key regulator of the alternative pathway of complement, in man and mouse. Earlier, our studies revealed that the absence of FH causes the C57BL6 mouse to become susceptible to chronic serum sickness (CSS) along with an increase in the renal infiltration of macrophages compared to controls. To understand if the increased recruitment of macrophages (Mϕs) to the kidney was driving inflammation and propagating injury, we examined the effect of Mϕ depletion with clodronate in FH knockout mice with CSS. Eight-week-old FHKO mice were treated with apoferritin (4 mg/mouse) for 5 wks and with either vehicle (PBS) or clodronate (50 mg/kg ip, 3 times/wk for the last 3 weeks). The administration of clodronate decreased monocytes and Mϕs in the kidneys by >80%. Kidney function assessed by BUN and albumin remained closer to normal on depletion of Mϕs. Clodronate treatment prevented the alteration in cytokines, TNFα and IL-6, and increase in gene expression of connective tissue growth factor (CTGF), TGFß-1, matrix metalloproteinase-9 (MMP9), fibronectin, laminin, and collagen in FHKO mice with CSS (P < 0.05). Clodronate treatment led to relative protection from immune complex- (IC-) mediated disease pathology during CSS as assessed by the significantly reduced glomerular pathology (GN) and extracellular matrix. Our results suggest that complement activation is one of the mechanism that regulates the macrophage landscape and thereby fibrosis. The exact mechanism remains to be deciphered. In brief, our data shows that Mϕs play a critical role in FH-dependent ICGN and Mϕ depletion reduces disease progression.

Quantification of Glomerular Structural Lesions: Associations With Clinical Outcomes and Transcriptomic Profiles in Nephrotic Syndrome.

RATIONALE & OBJECTIVE: The current classification system for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) does not fully capture the complex structural changes in kidney biopsies nor the clinical and molecular heterogeneity of these diseases. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 221 MCD and FSGS patients enrolled in the Nephrotic Syndrome Study Network (NEPTUNE). EXPOSURE: The NEPTUNE Digital Pathology Scoring System (NDPSS) was applied to generate scores for 37 glomerular descriptors. OUTCOME: Time from biopsy to complete proteinuria remission, time from biopsy to kidney disease progression (40% estimated glomerular filtration rate [eGFR] decline or kidney failure), and eGFR over time. ANALYTICAL APPROACH: Cluster analysis was used to group patients with similar morphologic characteristics. Glomerular descriptors and patient clusters were assessed for associations with outcomes using adjusted Cox models and linear mixed models. Messenger RNA from glomerular tissue was used to assess differentially expressed genes between clusters and identify genes associated with individual descriptors driving cluster membership. RESULTS: Three clusters were identified: X (n = 56), Y (n = 68), and Z (n = 97). Clusters Y and Z had higher probabilities of proteinuria remission (HRs of 1.95 [95% CI, 0.99-3.85] and 3.29 [95% CI, 1.52-7.13], respectively), lower hazards of disease progression (HRs of 0.22 [95% CI, 0.08-0.57] and 0.11 [95% CI, 0.03-0.45], respectively), and lower loss of eGFR over time compared with X. Cluster X had 1,920 genes that were differentially expressed compared with Y+Z; these reflected activation of pathways of immune response and inflammation. Six descriptors driving the clusters individually correlated with clinical outcomes and gene expression. LIMITATIONS: Low prevalence of some descriptors and biopsy at a single time point. CONCLUSIONS: The NDPSS allows for categorization of FSGS/MCD patients into clinically and biologically relevant subgroups, and uncovers histologic parameters associated with clinical outcomes and molecular signatures not included in current classification systems.

Mouse Homologue of Human HLA-DO Does Not Preempt Autoimmunity but Controls Murine Gammaherpesvirus MHV68.

H2-O (human HLA-DO) is a relatively conserved nonclassical MHC class II (MHCII)-like molecule. H2-O interaction with human HLA-DM edits the repertoire of peptides presented to TCRs by MHCII. It was long hypothesized that human HLA-DM inhibition by H2-O provides protection from autoimmunity by preventing binding of the high-affinity self-peptides to MHCII. The available evidence supporting this hypothesis, however, was inconclusive. A possibility still remained that the effect of H2-O deficiency on autoimmunity could be better revealed by using H2-O-deficient mice that were already genetically predisposed to autoimmunity. In this study, we generated and used autoimmunity-prone mouse models for systemic lupus erythematosus and organ-specific autoimmunity (type 1 diabetes and multiple sclerosis) to definitively test whether H2-O prevents autoimmune pathology. Whereas our data failed to support any significance of H2-O in protection from autoimmunity, we found that it was critical for controlling a γ-herpesvirus, MHV68. Thus, we propose that H2-O editing of the MHCII peptide repertoire may have evolved as a safeguard against specific highly prevalent viral pathogens.

Myeloperoxidase immunohistochemical staining can identify glomerular endothelial cell injury in dense deposit disease.

BACKGROUND: 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. CASE (DIAGNOSIS/TREATMENT): 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. CONCLUSION: 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.

Multicenter study of risk factors of unplanned 30-day readmissions in pediatric oncology.

BACKGROUND: Pediatric oncology patients have high rates of hospital readmission but there is a dearth of research into risk factors for unplanned 30-day readmissions among this high-risk population. AIM: In this study, we built a statistical model to provide insight into risk factors of unplanned readmissions in this pediatric oncology. METHODS: We retrieved 32 667 encounters from 10 418 pediatric patients with a neoplastic condition from 16 hospitals in the Cerner Health Facts Database and built a mixed-effects model with patients nested within hospitals for inference on 75% of the data and reserved the remaining as an independent test dataset. RESULTS: The mixed-effects model indicated that patients with acute lymphoid leukemia (in relapse), neuroblastoma, rhabdomyosarcoma, or bone/cartilage cancer have increased odds of readmission. The number of cancer medications taken by the patient and the administration of chemotherapy were associated with increased odds of readmission for all cancer types. Wilms Tumor had a significant interaction with administration of chemotherapy, indicating that the risk due to chemotherapy is exacerbated in patients with Wilms Tumor. A second two-way interaction between recent history of chemotherapy treatment and infections was associated with increased odds of readmission. The area under the receiver operator characteristic curve (and corresponding 95% confidence interval) of the mixed-effects model was 0.714 (0.702, 0.725) on the independent test dataset. CONCLUSION: Readmission risk in oncology is modified by the specific type of cancer, current and past administration of chemotherapy, and increased health care utilization. Oncology-specific models can provide decision support where model built on other or mixed population has failed.

Discordance between immunofluorescence and immunohistochemistry C4d staining and outcomes following heart transplantation.

BACKGROUND: Capillary deposition of C4d is an important marker of antibody-mediated rejection (AMR) following heart transplantation (HT). There are two immunopathologic assay methods for detecting C4d: frozen-tissue immunofluorescence (IF) and paraffin immunohistochemistry (IHC). The clinical significance of discrepancy between the results of IF and IHC has not been understood. METHODS AND RESULTS: We reviewed 2187 biopsies from 142 HT recipients who had biopsies with assessment of both IF and IHC staining. Among them, 103 (73%) patients had negative IF and IHC C4d staining (Negative Group) and 32 (23%) patients had positive IF but negative IHC staining (Discordant Group). At the time of positive biopsy, 6 (19%) Discordant patients had graft dysfunction, compared to 5 (5%) Negative patients (p = .022). Cumulative incidence of cellular rejection at 1 year was comparable (31% vs. 29%, p = .46); however, cumulative incidence of AMR was significantly higher in the Discordant group (21% vs. 4%, p = .004). Overall 1-year survival was comparable (90% vs. 96%, p = .24); however, freedom from heart failure (HF) was significantly lower in the Discordant group (70% vs. 96%, p < .001). CONCLUSION: The Discordant group showed higher rates of graft dysfunction, AMR and HF admission than the Negative group.

Arterial Intimal Fibrosis in Reperfusion Biopsy Correlates with Graft Function after Kidney Transplant.

INTRODUCTION: Alterations to the procurement biopsy are one of the main reasons that kidneys are not suitable for transplant and are discarded. The literature on procurement and reperfusion biopsy is inconsistent and heterogeneous. The objective of this study is to describe the correlation of the different histological characteristics detected by the procurement and reperfusion biopsies in relation to graft function. METHODS: This is a retrospective cohort study of deceased donor kidney transplants performed from 2013 to 2017. All of the different histological components of procurement and reperfusion biopsies were analyzed with nonparametric tests and multivariate regressions. Graft function was expressed as glomerular filtration rate (GFR) at 1, 3, 6, and 12 months after transplant. All tests were based on a level of significance of α = 0.05. RESULTS: A comparison of procurement and reperfusion biopsies revealed that 60.4% of the grafts exhibited more arterial intimal fibrosis and 55.6% more arteriolar hyalinosis in the reperfusion biopsy than in the procurement biopsy. Arterial intimal fibrosis in reperfusion biopsy correlated with GFR at all time points, and it was the only histological characteristic of the reperfusion biopsy that remained significant in multivariate analysis. Glomerulosclerosis in the procurement biopsy correlated with graft function and remained significant in multivariate analysis, but only at 6 months. Arterial intimal fibrosis in the reperfusion biopsy is significantly associated with graft function independently of clinical characteristics. CONCLUSION: Our study highlights the importance of arterial intimal fibrosis in predicting kidney function after transplant. Because arterial intimal fibrosis is a chronic change not related to ischemia-reperfusion injury, the differences between the 2 biopsies may be due to the biopsy technique. In order to increase the prognostic accuracy of the procurement biopsy, the technique should be improved to better evaluate the vasculature.

Infection-Related Glomerulonephritis.

Background: There has been a long, storied relationship between various bacterial infections and glomerular injury, which is now encompassed under the term of infection-related glomerulonephritis (GN). The clinical and pathologic manifestations vary depending on the duration, magnitude, and underlying pathogen associated with the inciting infectious process. A brief and acute episode may lead to a self-limiting glomerular manifestation while a chronic or repetitive infection can result in persistent and irreversible injury. In this review, we will discuss the clinical and pathologic findings associated with the infection-related glomerulonephritides. Summary: An acute exudative GN with an influx of neutrophils is the most characteristic morphologic alteration associated with infection-related glomerular injury. The immunofluorescence staining pattern often reveals prominent complement component C3 deposition in both capillary walls and mesangial regions with or without accompanying immunoglobulin. Large subepithelial electron-dense deposits known as "humps" are the hallmark ultrastructural finding; however, these features can also be present in C3 glomerulopathies, which are often triggered by infections and may have similar underlying abnormalities in alternative pathway complement activation. In addition, other glomerular injuries can simultaneously be present along with infection-related GN, such as diabetic nephropathy, lupus nephritis, or immunoglobulin A nephropathy, constituting a true diagnostic challenge for the pathologist. Key Messages: Bacterial infection-related GN represents a spectrum of glomerular injury with variable clinical and pathologic presentations. The pathologic findings can show overlap with other glomerular diseases, and different forms of infection-related GN vary in terms of prognosis and treatment approach.

The Importance of Nephropathology in Kidney Cancer.

As early detection and advances in the treatment for renal cell carcinoma continue to lead to excellent oncologic outcomes, the preservation of renal function in kidney cancer patients has emerged as an increasingly important clinical objective. Given that diabetes, hypertension, obesity, cigarette smoking, and aging are independent risk factors for renal cell carcinoma, the corresponding non-neoplastic kidney diseases frequently are present, but often undiagnosed. In addition, the subsequent clinical management of the ensuing chronic kidney disease historically has not included nephrologists. Awareness of these practice gaps remain low among nephrologists, surgeons, and pathologists. This article discusses the common non-neoplastic kidney diseases that are encountered in cancer nephrectomy specimens. The accurate and timely diagnosis of these disorders will result in additional gains in clinical outcomes. There is a unique opportunity for the nephrology community to play a central role in the management of chronic kidney disease that often is present in kidney cancer patients.

Soft-Tissue Tumors of the Hand-Imaging Features.

Imaging studies of the hands and fingers are common, and radiologists are generally comfortable with traumatic and degenerative conditions which arise frequently in daily practice. However, a variety of common and uncommon soft-tissue tumors also occur in the hand, the appropriate diagnosis of which can be a source of confusion for both clinicians and radiologists. These lesions often have overlapping imaging characteristics; however, a structured approach can help provide a focused differential diagnosis and impact further workup and management. We discuss several such tumors, categorizing them as cystic-appearing, noncystic masses along tendons and aponeuroses, adipocytic tumors, vascular lesions, and miscellaneous lesions with imaging features that can aid diagnosis.

A New Paradigm for Renal Thrombotic Microangiopathy.

Thrombotic microangiopathy (TMA) is characterized by thrombocytopenia and microangiopathic hemolytic anemia, results from acute and/or chronic endothelial cell injury, and often manifests with kidney dysfunction. TMA can be observed in a wide spectrum of clinical scenarios, which includes but is not limited to thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, severe (malignant) hypertension, preeclampsia/eclampsia, antiphospholipid antibody syndrome, scleroderma renal crisis, drug toxicities, or metabolic disorders. These different conditions are impossible to distinguish based solely on the pathologic findings, necessitating correlation with clinical and laboratory data. For both treating physicians and pathologists, the absence of specific pathologic features for a particular etiology or association with TMA remains a great source of frustration and confusion that currently accompanies this complex topic. In this review, we introduce a new paradigm for TMA that coalesces around the important contribution of the complement system, which has potential implications for therapeutic management, disease recurrence in the kidney allograft, and genetic risks to family members.

Chronic Microangiopathy Due to DCR-MYC, a Myc-Targeted Short Interfering RNA.

Thrombotic microangiopathy (TMA) is an emerging complication of oncologic therapy. Cancer-related causes of renal endothelial cell damage include cytotoxic chemotherapies, radiation given for myeloablation, and direct involvement of renal vasculature by tumor cells. Another class of therapeutic agents that has been implicated in TMA is the vascular endothelial growth factor (VEGF) pathway inhibitors, including the anti-VEGF monoclonal antibody bevacizumab and the VEGF receptor tyrosine kinase inhibitor sunitinib. These TMAs have been termed type II cancer drug-induced TMA and are distinguished from those associated with some cytotoxic chemotherapies (ie, type I) in that they are not dose dependent and patients are more likely to demonstrate some recovery of kidney function. Determination of the cause of TMA in oncologic patients often presents a significant challenge because patients frequently receive multiple chemotherapeutic agents simultaneously and clinicopathologic features often demonstrate substantial overlap, regardless of cause. We present a case of TMA with predominantly chronic features in a 70-year-old patient being treated for adenoid cystic carcinoma of the breast with a single agent, a short interfering RNA targeted against Myc (DCR-MYC).