Chimeric Antigen Receptor (CAR) T-Cell Therapy Use in Patients with Multiple Myeloma and Kidney Failure on Maintenance Hemodialysis: A Report of 2 Cases.

Chimeric antigen receptor (CAR) T-cell therapy against B-cell maturation antigen is a new treatment modality for relapsed or refractory multiple myeloma (MM). Patients with kidney failure and MM were excluded from the pivotal CAR T-cell therapy clinical trials: KaRMMa (idecabtagene vicleucel) and CARTITUDE (ciltacabtagene autocleucel). The safety and efficacy of CAR T-cell therapy in patients with relapsed or refractory MM and kidney failure are limited to a few case reports using idecabtagene vicleucel. Here, we report the first 2 cases of ciltacabtagene autoleucel use in patients with kidney failure on maintenance hemodialysis and relapsed or refractory MM. Both patients achieved a hematologic response following ciltacabtagene autoleucel administration without serious adverse events. These findings suggest that ciltacabtagene autoleucel may be safe and effective in patients with relapsed or refractory MM and kidney failure. In this report, we review the available literature regarding the use of CAR T-cell therapy in patients with MM and kidney failure. We also discuss the modification of the lymphodepletion regimen in the kidney failure setting.

Seronegative celiac disease with transient protein-losing enteropathy and vitamin B12 deficiency in a pediatric patient: Case report.

Key Clinical Message: Early recognition and management of seronegative celiac disease, even in the absence of typical serological markers, can prevent complications and ensure better health outcomes in pediatric patients. Consideration of a gluten-free diet in similar cases can lead to significant clinical improvement. Abstract: Celiac disease, characterized by its diverse clinical manifestations, often necessitates adherence to a gluten-free diet, particularly in pediatric patients for optimal growth and development. This report presents the case of an 11-year-old male who exhibited recurrent symptoms of fever and diarrhea progressing to edema and pallor, with a history dating back to age 3. Laboratory findings revealed pancytopenia, hypoalbuminemia, and proteinuria. Despite negative serological markers, noninvasive tests, along with clinical improvement on a gluten-free diet and supportive measures within a month, suggested celiac disease complicated by transient protein-losing enteropathy and vitamin B12 deficiency. It is important to note that other malabsorption disorders can also show clinical improvement following a gluten-free diet. Additionally, the antibiotic treatment received by the patient could have addressed other possible causes of malabsorption, complicating the differential diagnosis. This case highlights the importance of early recognition and management of celiac disease, especially in pediatric patients, to prevent complications and promote optimal health outcomes.

Immunotactoid Glomerulopathy.

Immunotactoid glomerulopathy (ITG) is a rare glomerular disease that typically presents with proteinuria, hematuria, and kidney dysfunction. A kidney biopsy is essential to establish the diagnosis of ITG. ITG is characterized by glomerular electron-dense immunoglobulin deposits with hollow-cored microtubules. ITG is classified as either monoclonal or polyclonal based on immunofluorescence staining of the immunoglobulin deposits. Monoclonal ITG is associated with an underlying hematologic disorder in two-thirds of the cases, lymphoma and plasma cell dyscrasias being the most common. Polyclonal ITG is associated with autoimmune diseases but can be seen with hematologic disorders and chronic infections. Due to the preponderance of hematologic disorders in both monoclonal and polyclonal ITG, a thorough hematologic workup must be performed in all cases of ITG. In monoclonal ITG with a detectable clone, clone-directed therapy is administered to achieve hematologic remission, as the renal response is highly dependent on the hematologic response. In clone-negative monoclonal ITG, anti-B cell therapy is often used as a first-line therapy. Management of polyclonal ITG without an underlying hematologic disorder is poorly defined. Compared to monoclonal ITG, patients with polyclonal ITG have a higher risk of progression to end-stage kidney disease. Recurrence of ITG following kidney transplantation is common and is often associated with hematologic relapse.

Real-World Experience With Avacopan in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

Introduction: Postmarketing data on outcomes of avacopan use in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) are lacking. Methods: We performed a multicenter retrospective analysis of 92 patients with newly diagnosed or relapsing AAV who received therapy with avacopan. The coprimary outcome measures were clinical remission at 26 and 52 weeks. We use descriptive statistics and univariate logistic regression to assess outcomes and predictors of remission, respectively. Results: Of the 92 patients, 23% (n = 21) had a baseline estimated glomerular filtration rate (eGFR) < 15 ml/min per 1.73 m2 and 10% on kidney replacement therapy at baseline. Among those with kidney involvement, mean (SD) enrollment eGFR was 33 (27) ml/min per 1.73 m2 with a mean (SD) change of +12 (25) and +20 (23) ml/min per 1.73 m2 at weeks 26 and 52, respectively. In addition to avacopan, 47% of patients received combination therapy of rituximab and low-dose cyclophosphamide, and 14% of patients received plasma exchange (PLEX). After induction, the median (interquartile range [IQR]) time to start avacopan was 3.6 (2.1-7.7) weeks, and the median time to discontinue prednisone after starting avacopan was 5.6 (3.3-9.5) weeks. Clinical remission was achieved in 90% of patients at week 26 and 84% of patients at week 52. Of the patients, 20% stopped avacopan due to adverse events, with the most common being elevated serum aminotransferases (4.3%). Conclusion: A high rate of remission and an acceptable safety profile were observed with the use of avacopan in the treatment of AAV in this postmarketing analysis, including the populations excluded from the ADVOCATE trial.

Unlocking the diagnostic, prognostic roles, and immune implications of BAX gene expression in pan-cancer analysis.

OBJECTIVES: Cancer, a formidable disease, continues to challenge our understanding and therapeutic approaches. This study delves into the pan-cancer analysis of BCL2 Associated X (BAX) gene expression, seeking to unravel its significance in cancer development, prognosis, and potential therapeutic strategies. METHODS: A combination of bioinformatics and molecular experiments. RESULTS: Our pan-cancer investigation into BAX expression encompassed 33 distinct cancer types, revealing a remarkable and uniform increase in BAX expression. This groundbreaking finding emphasizes the potential universality of BAX's role in cancer development and progression. Further, our study explored the prognostic implications of BAX expression, highlighting a consistent association between up-regulated BAX and poor overall survival (OS) in Liver Hepatocellular Carcinoma (LIHC) and Skin Cutaneous Melanoma (SKCM). These results suggest that BAX may serve as an adverse prognostic indicator in these malignancies, emphasizing the importance of personalized treatment strategies. Epigenetic and genetic analyses of BAX provided valuable insights. Hypomethylation of the BAX promoter region was evident in LIHC and SKCM, which likely contributes to the up-regulation of BAX, while genetic mutations in the BAX gene itself were infrequent in these cancers. Our exploration of BAX-associated signaling pathways and the correlation between BAX expression and CD8+ T cell infiltration shed light on the intricate molecular landscape of cancer. BAX's interaction with key apoptotic and immune-related pathways reinforces its role as a central player in tumor development and the immune microenvironment. Moreover, our drug prediction analysis identified potential therapeutic agents for modulating BAX expression in the context of LIHC and SKCM, bridging the gap between research and clinical application. CONCLUSION: In sum, our comprehensive BAX study not only enhances our understanding of its significance as a biomarker gene but also offers novel avenues for therapeutic interventions, contributing to the ongoing quest for more effective cancer treatments and improved patient care.

Pegylated Liposomal Doxorubicin Causes Kidney-limited Thrombotic Microangiopathy.

A definite causal link between pegylated liposomal doxorubicin (PLD) and kidney-limited thrombotic microangiopathy (TMA) remains unestablished. Here, we report 2 cases of PLD-induced kidney-limited TMA, 1 in a patient with myxofibrosarcoma and the other in a patient with liposarcoma. The 2 patients received a high cumulative dose of PLD, and both presented with a rise in serum creatinine and proteinuria. Kidney biopsy revealed TMA with chronic mesangiolysis and capillary wall double contouring. Neither patient had concomitant exposure to TMA-causing drugs, such as gemcitabine, anti-vascular endothelial growth factor agents, or mammalian target of rapamycin inhibitors. The work-up for secondary causes of TMA was negative in both patients. The cessation of PLD therapy led to improvement or stabilization in serum creatinine and proteinuria in both patients. These 2 cases provide a clear causal link between PLD and kidney-limited TMA. The high cumulative dose of PLD increases the risk of kidney TMA. Early recognition of PLD-induced kidney TMA can lead to timely cessation of PLD therapy and potentially preserve kidney function.

The role of stents in hemodialysis vascular access.

Vascular access is the Achilles' heel of dialysis therapy among patient with end stage kidney disease. The development of neointimal hyperplasia and subsequent stenosis is common in vascular access and is associated with significant morbidity. Percutaneous transluminal angioplasty using balloon inflation was the standard therapy of these lesions. However, the balloon-based approaches were associated with poor vascular access patency rate necessitating new inventions. It is within this context that different types of stents were developed in order to improve the overall dialysis vascular access functionality. In this article, we review the available literature regarding the use of stents in treating dialysis vascular access stenotic lesions. Further, we review the major clinical trials of stent use in different anatomic locations and in different clinical scenarios.

Role of Finerenone in the Treatment of Diabetic Kidney Disease: Patient Selection and Clinical Perspectives.

Diabetes is the leading cause of chronic and end stage kidney disease globally. Despite recent advances in therapies for diabetic kidney disease (DKD), there remains a critical need for additional options to improve renal and cardiovascular outcomes. Mineralocorticoid overactivation contributes to inflammation and fibrosis which in turn leads to progression of DKD. Finerenone, a novel non-steroidal mineralocorticoid receptor antagonist, has shown promising cardiac and renoprotective benefits in DKD. The utility of finerenone in the real world will require appropriate patient selection and patient monitoring by clinicians.

Endovascular Management of Thrombosed Dialysis Vascular Circuits.

A functional hemodialysis vascular access is the lifeline for patients with end-stage kidney disease and is considered a major determinant of survival and quality of life in this patient population. Hemodialysis therapy can be performed via arteriovenous fistulas, arteriovenous grafts, and central venous catheters (CVCs). Following dialysis vascular access creation, the interplay between several pathologic mechanisms can lead to vascular luminal obstruction due to neointimal hyperplasia with subsequent stenosis, stasis, and eventually access thrombosis. Restoration of the blood flow in the vascular access circuit via thrombectomy is crucial to avoid the use of CVCs and to prolong the life span of the vascular access conduits. The fundamental principles of thrombectomy center around removing the thrombus from the thrombosed access and treating the underlying culprit vascular stenosis. Several endovascular devices have been utilized to perform mechanical thrombectomy and have shown comparable outcomes. Standard angioplasty balloons remain the cornerstone for the treatment of stenotic vascular lesions. The utility of drug-coated balloons in dialysis vascular access remains unsettled due to conflicting results from randomized clinical trials. Stent grafts are used to treat resistant and recurrent stenotic lesions and to control extravasation from a ruptured vessel that is not controlled by conservative measures. Overall, endovascular thrombectomy is the preferred modality of treatment for the thrombosed dialysis vascular conduits.

Immunotherapies and Renal Injury.

Cancer immunotherapy represents a giant leap forward in the management of malignant diseases. An optimal anti-tumor immune response requires cancer antigen recognition by T-cells followed by an effector immune response. Suppression of T-cell activation prevents cancer cell clearance resulting in tumor proliferation. Recent clinical successes of immune checkpoint inhibitors and chimeric antigen receptor T cell therapies has transformed the landscape of cancer immunotherapy. The goal of immunotherapy is to boost host-protective anti-tumor immunity without concomitantly causing immune-related adverse events. However, immunotherapies can cause multiorgan dysfunction including acute kidney injury. Prompt recognition and management of immunotherapy-associated kidney injury is critical in preserving kidney function and improving patient outcomes.

Concordance Between Clinical and Pathological Response Assessment After Neo-Adjuvant Chemotherapy in Patients With Invasive Lobular Carcinoma.

Background Neo-adjuvant chemotherapy (NAC) is frequently administered in breast carcinoma patients. The clinical response to NAC guides further treatment. The pathological response is not only an independent prognostic factor, but it also guides further treatment and prognosis. Objectives The aim of our study was to find the degree of concordance between clinical and pathological response assessments after NAC in Invasive lobular Carcinoma (ILC) cases by using World Health Organization (WHO) criteria and different pathological systems, respectively. We also tried to identify any useful parameter of clinical assessment that could better correlate with pathologic assessment and provide a better estimation of residual tumor. Methods This retrospective study was conducted on 26 ILC tumors diagnosed in 24 patients who were treated with NAC followed by surgical resection between January 2009 and December 2020. Medical records and microscopy glass slides were reviewed for clinical and pathological response assessments, respectively. Results The pre-treatment tumor area ranged from 1.8-255 cm2 and the mean±SD was 52.2±66.8 cm2. After NAC, complete clinical response was observed in four (15.3%) cases. The clinically assessed mean tumor area significantly reduced from 52.2±66.8 cm2 to 17.2±22.6 cm2 (p-value<0.001). The pathologically assessed mean tumor area (27.4±24.1 cm2) didn't differ significantly from the clinically assessed mean tumor area (17.2±22.6 cm2) (p-value=0.114). Pathologically, the majority of the cases showed partial response, and a complete pathological response was achieved in only two (7.7%) cases. The concordance rates between clinical assessment by the WHO method and pathological assessment of the breast using the Sataloff method, Miller-Payne (MP) system, Residual Cancer Burden system, and Chevallier method were 26.7%, 15.8%, 9%, and 3.5%, respectively, with insignificant p-values. Percentage reduction in clinical size and percentage reduction in tumor cellularity differed significantly (p-value=0.038). Conclusion Clinical response assessment provides a less accurate estimation of residual disease, as it shows poor concordance with pathological assessment using different assessment systems/methods.

Current Paradigms and Emerging Opportunities in Nephrology Training.

Nephrology is facing a period of remarkable and unprecedented change. The pipeline of device and therapeutic drug development, the growing success of clinical trials, and the emergence of novel clinical practice and training pathways each hold the promise of transforming patient care. Nephrology is also at the forefront of health policy in the United States, given the recent Advancing American Kidney Health initiative. Despite these developments, significant barriers exist to ensure a robust pipeline of well-qualified nephrologists, including but not limited to trainees' declining trainee interest in the specialty, lower board pass rates, and a perceived erosion in stature of the subspecialty. There is a lack of consensus among training program directors regarding procedural training requirements, the number of fellowship positions needed, and the value of the match. There is widespread agreement, however, that any initiative to reassert the value of nephrology must include significant focus on reinvigorating the trainee experience before and during fellowship. We discuss the current state of education in nephrology (from medical school to beyond fellowship) and highlight ways to increase interest in nephrology to reinvigorate the specialty.

New Directions in Ensuring Catheter Safety.

Tunneled dialysis catheters remain the most common vascular access used to initiate hemodialysis. Unfortunately, their use is associated with higher morbidity and mortality when compared with arteriovenous fistulae or grafts. Different types of catheters with different designs and material properties function differently. Additional devices and medications can be used to decrease the rates of infection and thrombosis. The current available tunneled dialysis catheters remain far from the desired goal and innovation in the field of dialysis vascular access remains in dire need.

Mycobacterium Abscessus: A Rare Cause of Peri-Ductal Mastitis in Endemic Regions.

Mycobacterium abscessus is a rapidly growing non-tuberculous, multi-drug resistant mycobacterium (NTM). Its common clinical presentation includes pulmonary infection followed by wide spectrum of skin and soft tissue infections. Chronic breast conditions, such as peri-ductal mastitis are rarely caused by NTM. Due to an intrinsic and acquired drug resistance to conventional antibiotics and anti-tuberculous therapy, it is often managed with a combination of antibiotics with or without surgical adjuncts. It is important to consider NTM in patients with chronic mastitis who show suboptimal response to initial broad-spectrum antibiotics, and especially when symptoms recur after complete resolution. This case report describes peri-ductal mastitis caused by mycobacterium abscessus in a 32-year female presenting with a history of painful breast lump and blood stained discharge. With initial diagnosis of nonspecific abscess, she received antibiotic therapy for 4 days at community healthcare setting without promising response. Subsequently, she was diagnosed as a case of peri-ductal mastitis for which quadrantectomy was performed; and surprisingly mycobacterium abscessus was identified on AFB culture. Full recovery was obtained with combination of antibiotics for prolonged period due to frequent relapses. Key Words: Mastitis, Mycobacterium abscessus, Non-tuberculous mycobacteria.

Pre-operative peritoneal drainage as a part of resuscitation in severe peritonitis.

The objective of this prospective observational study was to evaluate the benefits of peritoneal drainage under ultrasonic guidance in cases of severe peritonitis. Fifty cases with peritonitis were included in this study, who were unfit for general anaesthesia, i.e. American Society for Anesthesiologists (ASA) IV plus. The results showed improvement in general condition of the patients in the terms of improved respiration, decreased abdominal distension and circulation. Thus, it was concluded that peritoneal intubation dramatically decreases abdominal distension. Drainage of septic fluid decreases the sepsis, resulting in improvement of organ functions. This procedure has been found to be beneficial and helpful as a supportive procedure in cases where immediate major surgical procedures like laparotomy are not possible due to comorbidities and unstable general condition.

Acquired Fanconi syndrome after treatment with capecitabine, irinotecan, and bevacizumab.

OBJECTIVE: To describe a case of acquired Fanconi syndrome after treatment with capecitabine, irinotecan, and bevacizumab. CASE SUMMARY: A 77-year-old female with metastatic colon cancer presented with vomiting and diarrhea. The patient had been diagnosed with stage IIIC (T3, N2, M0) colon cancer 18 months earlier and was initially treated with FOLFOX6 (regimen of oxaliplatin, fluorouracil, and leucovorin) after her hemicolectomy. She was switched to a capecitabine/oxaliplatin regimen after 4 cycles due to central access problems. She did well until 10 months after her cancer diagnosis, when metastasis was discovered. She was started on reduced doses of capecitabine, irinotecan, and bevacizumab. After her eleventh cycle, she presented to the hospital with the above symptoms. Laboratory test results showed hypokalemia, hypocalcemia, hypophosphatemia, and hypouricemia. The patient had not been started on any new medications other than chemotherapy for over 1 year. The electrolyte derangements were new, since the patient had laboratory values checked every 3 weeks. Despite daily intravenous replacements, the electrolyte abnormalities persisted. Laboratory evaluations demonstrated the presence of euglycemic glucosuria and a high fractional excretion of phosphorus in the setting of hypophosphatemia. Fanconi syndrome was confirmed by demonstration of aminoaciduria. DISCUSSION: Fanconi syndrome is a disorder characterized by proximal tubular dysfunction resulting in electrolyte wasting. In the acquired form, medications and multiple myeloma are the most common causes. Based on the Naranjo probability scale, a drug was the probable cause of Fanconi syndrome in our patient. However, because multiple drugs were involved, it was not possible to determine which one was the culprit. CONCLUSIONS: This is the first case of Fanconi syndrome reported after the administration of capecitabine, irinotecan, and bevacizumab. More studies are needed to confirm this association.