Giant cell myocarditis (GCM) and cardiac sarcoidosis (CS) are rare, inflammatory cardiomyopathies with overlapping presentations but differing treatments and prognoses. We present a case of a middle-aged woman diagnosed initially with GCM based on clinical presentation and endomyocardial biopsy. After unexpected clinical improvement and persistent mediastinal lymphadenopathy, lymph node biopsy revealed non-necrotizing granulomas, leading to a revised diagnosis of CS. This case highlights the diagnostic challenges presented by inflammatory cardiomyopathies and the importance of reassessing initial diagnoses in the context of evolving clinical and imaging findings. Herein we detail her clinical course, and the investigations and therapeutic interventions undertaken.

Background: Hydroxychloroquine (HCQ) is widely used to manage autoimmune conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren’s syndrome. However, HCQ can cause cardiotoxicity, a dose-dependent complication linked to the accumulation of metabolites in lysosomes that alters cellular pH. HCQ-induced cardiotoxicity can lead to various cardiac abnormalities, including conduction defects, hypertrophy, and heart failure (HF). Importantly, this toxicity may be reversible with early detection and prompt discontinuation of HCQ. Case Summary: Three cases of SLE patients with prolonged HCQ use are presented, all of whom exhibited signs of cardiomyopathy and HF. The first case involved a 70-year-old male with a 30-year history of HCQ use, who presented with Mobitz II A-V block and other cardiac abnormalities. The second case was a 45-year-old female with a 26-year history of HCQ therapy who developed sinus tachycardia and biatrial enlargement. The third case involved a 75-year-old woman with 30 years of HCQ use, presenting with shortness of breath and pulmonary hypertension. In all cases, HCQ was discontinued, and supportive HF therapy was initiated, leading to improved ejection fraction and resolution of symptoms within months. Discussion: HCQ cardiotoxicity, although rare, is an important consideration in patients on long-term therapy, particularly as it is potentially reversible. The diagnosis can be challenging due to the nonspecific nature of cardiac symptoms and overlaps with other conditions. Imaging, particularly cardiac magnetic resonance imaging, plays a crucial role in early detection, while endomyocardial biopsy provides a definitive diagnosis. These cases underscore the need for clinicians to be aware of HCQ cardiotoxicity, as early intervention can improve patient outcomes.

Abstract Disclosure: D. He: None. J. Pullman: None. S. Stefan: None. B.Y. Wong: None. Background: Pheochromocytomas are catecholamine-secreting tumors that arise from chromaffin cells in the adrenal medulla or paraganglia. Representing 1-9% of pheochromocytomas, composite pheochromocytomas are rare tumors composed of pheochromocytoma and neural tumor components such as neuroblastoma, ganglioneuroblastoma, ganglioneuroma or peripheral nerve sheath tumor1. We present a case of composite pheochromocytoma and ganglioneuroma. Clinical Case: A 69-year-old man presented with recurrent dyspnea at rest, diaphoresis and tachycardia. He was diagnosed with heart failure with reduced ejection fraction and management included metoprolol 50 mg daily. On work-up, he was incidentally found to have a 1.2 cm left upper lobe lung lesion and an indeterminate 2.4 cm right adrenal mass on CTA chest. PET/CT scan showed an intensely avid left upper lobe lung nodule and a right adrenal mass with mild FDG uptake (SUV max 3.8). MRI abdomen demonstrated a 3.1 cm right adrenal lesion with a mildly thickened enhancing rim and a central enhancing nodular component suspicious for pheochromocytoma, metastases, schwannoma or ganglioneuroma. He then had a stroke with mild residual right-sided weakness. Oncological work-up of his lung and adrenal lesions eventually directed tissue sampling to biopsy of the adrenal lesion and pathology was consistent with pheochromocytoma. Subsequent biochemical evaluation revealed elevated plasma metanephrines of 194 pg/mL (<= 57 pg/mL), plasma normetanephrines of 474 pg/mL (<= 148 pg/mL), 24-hour urine metanephrines of 389 mcg (90-315 mcg) and 24-hour urine normetanephrines of 428 mcg (122-676 mcg). Pre-operatively, he was placed on phenoxybenazmine 10 mg twice daily and metoprolol 62.5 mg every 8 hours. The patient then underwent right adrenalectomy. The tumor nodule was adherent to and dissected off the inferior vena cava. Pathology showed composite pheochromocytoma with a small component of ganglioneuroma. Conclusion: This rare case of a composite pheochromocytoma with ganglioneuroma was diagnosed through histopathology as composite pheochromocytomas are clinically and radiographically indistinguishable from pheochromocytomas1. Management of composite pheochromocytomas with ganglioneuroma is similar to the management of pheochromocytomas, and surgical resection remains the first line treatment. Combined alpha and beta-adrenergic blockade is recommended to prevent intraoperative hypertensive crisis. However, more studies are needed to further understand these rare composite pheochromocytomas. References: 1.Shida Y, Igawa T, Abe K, Hakariya T, Takehara K, Onita T, Sakai H. Composite pheochromocytoma of the adrenal gland: a case series. BMC Res Notes. 2015 Jun 24;8:257. doi: 10.1186/s13104-015-1233-6. PMID: 26104921; PMCID: PMC4477526. Presentation: Friday, June 16, 2023

PDF file - 77K, Supplementary Table 1: Clinical and Pathological characteristics of tumor samples. Supplementary Table 2: Aberrantly methylated and underexpressed loci with overlapping enhancer (H3K4me1) marks. Supplementary Table 3: Transcription factor binding sites enriched in differentially methylated regions in RCC. Supplementary Table 4: List of Gene and Pathways hypermethylated and underexpressed in RCC. Supplementary Table 5: Genes deleted in RCC. Supplementary Table 6: Genes amplified in RCC.

Introduction Treatment failures for lupus nephritis (LN) are high with 10%–30% of patients progressing to end-stage renal disease (ESRD) within 10 years. Interstitial fibrosis/tubular atrophy (IFTA) is a predictor of progression to ESRD. Prior studies suggest that tubulointerstitial injury secondary to proteinuria in LN is mediated by complement activation in the tubules, specifically through the membrane attack complex (MAC). This study aimed to investigate the associations between tubular MAC deposition with IFTA and proteinuria. Methods In this cross-sectional study, LN kidney biopsies were assessed for MAC deposition by staining for Complement C9, a component of the MAC. Chromogenic immunohistochemistry was performed on paraffin-embedded human renal biopsy sections using unconjugated, murine anti-human Complement C9 (Hycult Biotech, clone X197). Tubular C9 staining intensity was analysed as present versus absent. IFTA was defined as minimal (<10%), mild (10%–24%), moderate (25%–50%) and severe (>50%). Results Renal biopsies from 30 patients with LN were studied. There were 24 (80%) female sex, mean age (SD) was 33 (12) years old and 23 (77%) had pure/mixed proliferative LN. Tubular C9 staining was present in 7 (23%) biopsies. 27 patients had minimal-to-mild IFTA and 3 patients had moderate IFTA. Among the C9 + patients, 3 (43%) had moderate IFTA as compared with none in the C9- group, p=0.009. C9 + patients had higher median (IQR) proteinuria as compared with C9- patients: 6.2 g (3.3–13.1) vs 2.4 g (1.3–4.6), p=0.001 at the time of biopsy. There was no difference in estimated glomerular filtration rate (eGFR) between the C9 + and C9- groups. Conclusion This study demonstrated that tubular MAC deposition is associated with higher degree of IFTA and proteinuria, which are predictors of progression to ESRD. These results suggest that tubular MAC deposition may be useful in classification of LN. Understanding the role of complement in tubulointerstitial injury will also identify new avenues for LN treatment.

Significance This study demonstrates that underexpression of succinate dehydrogenase (SDH) subunits resulting in accumulation of oncogenic succinate is a common, adverse, epigenetic modulating feature in clear cell renal cell carcinoma (ccRCC), during pathogenesis and progression. The study sheds light on the mechanisms of down-regulation of SDH subunits in ccRCC and deciphers the consequent oncogenic effects. It shows that functional SDH deficiency is a common feature of ccRCC (∼80% of all kidney cancers), and not just limited to the 0.05 to 0.5% of kidney cancers with germline SDH mutations.

Objectives To assess student outcomes and experiences, as well as preceptor experiences, after emergently converting a preclinical medical school renal course to a remote setting during the COVID-19 pandemic. Methods First-year medical student examination scores and responses to Likert-scale questions on end-of-course evaluations from the 2018–2019 (traditional) and 2019–2020 (remote) academic years were compared. Free-text responses from students and preceptors were analyzed using a qualitative summative approach to extract major themes in perceptions of remote learning. Results Mean student scores on course examinations did not significantly differ between the traditional and remote settings ( p = 0.23 and 0.84 respectively). Quantitative analysis of student evaluations revealed no significant difference across all items in mean Likert-scale responses. Student and preceptor free-text responses identified course leader engagement and responsiveness as essential to the success of remote-based learning. Optimal group size and online etiquette are areas that require attention. Conclusions Despite rapid conversion of a preclinical medical school renal course to a remote-based format in the setting of the COVID-19 pandemic, student scores and evaluations remain positive and largely unchanged.

ABSTRACT Background Reduced succinate dehydrogenase (SDH) activity resulting in adverse succinate accumulation was previously thought to be relevant only in 0.05-0.5% of kidney cancers associated with germline SDH mutations (categorized ‘SDH-deficient Renal Cell Carcinoma’ in the 2016 WHO classification) Results We show that under-expression of SDH subunits resulting in accumulation of oncogenic succinate is a common feature in clear cell renal cell carcinoma (ccRCC) tumors during pathogenesis and progression, with a marked adverse impact on survival in a large cohort (n=516) of ccRCC patients. From a mechanistic standpoint, we show that von Hippel-Lindau (VHL) loss induced hypoxia-inducible factor (HIF) dependent upregulation of mir-210 in ccRCC causes direct inhibition of the SDHD transcript. We demonstrate that reduced expression of SDH subunits is associated with genome-wide increase in methylation and enhancement of epithelial mesenchymal transition (EMT) in ccRCC tumors, consistent with succinate-induced inhibition of TET activity and increase in invasiveness/ migratory ability of ccRCC cells. TET-2 inhibition-induced global regulatory DNA hypermethylation drives SDH loss-induced enrichment of EMT. SDH subunits under-expression had a striking association with CDHI (E-cadherin) loss in ccRCC tumors, in keeping with succinate-induced CDH1 hypermethylation and under-expression in ccRCC cells. Next, in conformity with recombinant TET-2 fluorescence quenching dynamics with succinate and ascorbic acid (AA, a TET enzyme co-factor), AA treatment led to reversal of succinate-induced inhibition of TET activity, CDH1 hypermethylation and under-expression, as well as enhanced invasiveness in ccRCC cells. Furthermore, using immunohistochemical analysis and artificial intelligence quantitation, we report that ccRCC is characterized by a marked loss of ascorbic acid transporter SLC23A1 [median percent positive cells in ccRCC primary tumors (n=104) and normal kidney cortex (n=7) was 0.7 and 32.4 respectively; p=0.0012]. Lower SLC23A1 was associated with worse survival in ccRCC (TCGA). Lastly, intravenous AA significantly prolonged survival in a metastatic ccRCC xenograft model with increased succinate and reduced SLC23A1 expression. Conclusions Taken together, these findings strongly indicate that functional SDH deficiency is a pathognomonic adverse feature of ccRCC (which accounts for ∼80% of all kidney cancers), and that the WHO category ‘SDH-deficient RCC’ should be re-named ‘ SDH germline mutation-associated RCC’. Furthermore, oncogenic accumulation of succinate can be abrogated by TET modulation with AA. STATEMENT OF SIGNIFICANCE In this study, we show that under-expression of succinate dehydrogenase (SDH) subunits resulting in the accumulation of oncogenic succinate is a common, adverse, epigenetic modulating feature occurring in a vast majority of clear cell renal cell carcinoma (ccRCC), during pathogenesis and progression. Functional SDH deficiency is therefore a pathognomonic feature of ccRCC (which accounts for ∼80% of all kidney cancers), and not just limited to the 0.05-0.5% of kidney cancer patients with germline SDH mutations. Based on the findings reported, we propose that the ‘SDH-deficient RCC’ category in the 2016 WHO classification of kidney tumors be renamed ‘SDH germline mutation-associated RCC’. Furthermore, we demonstrate that oncogenic accumulation of succinate in ccRCC can be countered by TET modulation with ascorbic acid, and that ccRCC is characterized by a marked loss of ascorbic acid transporter SLC23A1. Graphical abstract depicting the consequential adverse downregulation of Succinate Dehydrogenase in ccRCC and its central role in oxidative phosphorylation