Adenosine deaminase 2 (ADA2) is predominantly expressed by and secreted from activated monocytes and macrophages into plasma. This review explores the utility of ADA2 as a biomarker of monocyte/macrophage activation in a range of conditions and suggests potential applications for its clinical use. Elevated ADA2 activity has been observed in conditions associated with granulomatous inflammation and macrophage activation, including tuberculosis, sarcoidosis, and macrophage activation syndrome. This finding has also been reported in liver fibrosis, malignancy, infection, and autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Absent or near absent ADA2 activity is associated with deficiency of ADA2 (DADA2), an autosomal recessive inborn error of immunity. Increased ADA2 activity correlates with monocyte/macrophage activity, making it a potential biomarker in diseases characterized by excessive macrophage activation. Although ADA2 activity is relatively easy to measure in plasma and may assist with diagnosis when conventional approaches are unavailable, invasive, or carry additional risks, it lacks disease specificity. The absence of ADA2 activity in plasma combined with a characteristic clinical phenotype and biallelic genetic mutations inADA2 is diagnostic of DADA2.

The co-occurrence of lupus nephritis (LN) and chronic kidney disease (CKD) is associated with an excess risk of infection. However, it remains unknown whether the infection risk differs between LN with moderate and advanced CKD (LN-CKD) and other CKD etiologies. Using data from the Swedish Renal registry 2006-2021, we identified 14,128 patients (median age 68 years, 64% men, median estimated glomerular filtration rate 25 ml/min per 1.73m2) that included 317 patients with LN-CKD, 783 patients with anti-neutrophil cytoplasm antibodies (ANCA) vasculitis , 8877 patients with diabetic kidney disease (DKD), 1855 patients with autosomal dominant polycystic kidney disease (ADPKD) and 2296 patients with primary glomerular disease (PGD). Multivariable Poisson models and cause-specific Cox proportional hazards regressions were used to compare the risk of all-cause- and site-specific infection-related hospitalizations (including sepsis, respiratory-, genitourinary-, gastrointestinal related infections and infection of other/unspecified sites), and death due to infection, between patients with LN-CKD and the other CKD etiologies. In LN-CKD, the three-year absolute risks of all-cause infection-related hospitalization and death due to infection were 31% and 4% respectively. The risk of all-cause infection-hospitalization was higher in LN-CKD than in ANCA vasculitis but similar between LN-CKD and DKD. LN-CKD was associated with a higher risk of all-cause infection-related hospitalization and death due to infection than ADPDK (adjusted hazard ratio 1.46 [1.18-1.8] and 2.47 [1.35-4.5], respectively) and PGD (1.90 [1.54-2.34] and 2.97 [1.71- 5.18], respectively). The results were consistent across the site-specific infection-related hospitalizations. Patients with LN exhibited a higher risk of severe infection compared to patients with ANCA vasculitis, ADPKD and PGD. LN-CKD and DKD had similar infection-risks. This highlights the need for prevention and tailored immunosuppressive therapy in the LN-population with CKD.

Niemann-Pick disease type B (NPD B) is a rare autosomal recessive disorder. It is clinically characterized by hepatosplenomegaly, interstitial lung disease, and thrombocytopenia. Its clinical features may overlap with those of autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Granulomatosis with Polyangiitis (GPA). In this context, we report the first documented case of a 51-year-old woman presenting with the association of NPD B, SLE, and probable GPA. Clinically, the patient exhibited dyspnea, severe anemia, hepatosplenomegaly, Jaccoud's arthropathy, and crusted rhinitis. Laboratory tests were positive for antinuclear antibodies and anti-neutrophil cytoplasmic antigens. Radiological examinations showed interstitial pneumonia and pansinusitis. NPD B was suspected based on the presence of sea-blue histiocytes in bone marrow biopsy and confirmed by sphingomyelinase deficiency. After six months of corticosteroid and hydroxychloroquine therapy, the patient showed significant improvement. This case highlights the importance of considering rare diseases in differential diagnosis, even when clinical signs suggest more common conditions.

Chronic kidney disease (CKD), characterized by structural, functional, and metabolic derangements, remains a leading cause of end-stage renal disease (ESRD) with profound global health burdens. The kidney's high oxygen demand for blood filtration renders it exquisitely sensitive to redox imbalance-an aberration common to both CKD and acute kidney injury (AKI) that, when coupled with iron dysregulation, unleashes ferroptosis: a non-apoptotic, iron-dependent form of regulated cell death driven by iron accumulation, lipid peroxidation, and antioxidant defense impairment (e.g., GPX4/SLC7A11 dysfunction), cascades to which the redox-sensitive kidney is uniquely predisposed. While ferroptosis has been linked to AKI, diabetic nephropathy (DN), and renal fibrosis, existing reviews largely suffer from two limitations: they either focus on single kidney disease entities (e.g., only AKI or DN) or reiterate generic ferroptosis mechanisms, lacking a unified pathophysiological framework that bridges acute insults, chronic fibrosis, and even renal carcinogenesis. Addressing this gap, this review offers three integrated contributions: first, it positions ferroptosis as a convergent metabolic executioner across a broader spectrum of kidney diseases-encompassing AKI, DN, renal interstitial fibrosis, systemic lupus erythematosus (SLE) nephritis, autosomal dominant polycystic kidney disease (ADPKD), renal cell carcinoma (RCC), and contrast-induced nephropathy (CIN)-while emphasizing cell type-specific vulnerabilities: tubular epithelial cells (susceptible via mitochondrial dysfunction), podocytes (via iron overload), and immune cells (e.g., neutrophils/macrophages in SLE nephritis) exhibit context-dependent ferroptosis regulation, governed by cell type-specific modulators [e.g., Nrf2 in tubules, heme oxygenase-1 (HO-1) in macrophages, and sirtuins in podocytes]. Second, it reconciles seemingly disparate findings through a redox-metabolic lens-e.g., dual roles of HO-1 (protective via heme degradation vs. pro-ferroptotic via iron release) or iron overload (driving injury in AKI vs. targeted therapy in RCC)-by clarifying disease-specific regulatory mechanisms: PKD1 mutation-driven mitochondrial defects in ADPKD, DPP9-Nrf2-mediated sorafenib resistance in RCC, and PPARα-FABP1 axis dysregulation in IgA nephropathy, alongside shared core pathways (e.g., GPX4/SLC7A11 as central checkpoints). Third, it integrates translational insights rarely synthesized in prior work: mapping natural compounds (icariin II and artesunate), repurposed drugs (sorafenib and melatonin), and novel modulators to disease stages (e.g., Lip-1 for fibrosis and salinomycin for RCC stem cells); highlighting strategies to reverse ferroptosis-related drug resistance (targeting DPP9 in RCC); and identifying ferroptosis-related genes (ACSL4 and PDIA4) as prognostic biomarkers. Accumulating clinical and experimental evidence confirms ferroptosis as a pivotal driver of kidney disease onset and progression. This review not only synthesizes ferroptosis pathophysiology and research advances but also delineates disease-tailored therapeutic strategies. By addressing key knowledge gaps-crosstalk between ferroptosis and other cell death modalities (e.g., pyroptosis), lack of kidney-specific clinical biomarkers, and underexplored roles in autoimmune nephritides-it provides a conceptual roadmap for mechanism-based diagnostics, precision therapeutics, and rational drug combinations, transcending traditional disease boundaries to advance clinical translation for both primary and secondary kidney diseases.

BackgroundMonogenic lupus is a rare form caused by single pathogenic gene variants, leading to diverse clinical symptoms from multi-organ involvement. Variants in Protein Kinase Cδ (PRKCD) are known contributors, though remain underreported.ObjectiveTo describe the phenotypic, genetic, and outcome profiles of Arab children with monogenic lupus and PRKCD deficiency.MethodsWe retrospectively reviewed medical records of children with PRKCD deficiency lupus at two institutions in Saudi Arabia and Oman. The cohort included genetically confirmed and clinically suspected cases (due to unavailable testing in deceased siblings). Demographic, clinical, genetic, and follow-up outcome data were collected and analyzed.ResultsSeven children (four females) from three unrelated consanguineous Arab families were identified, with four having confirmed PRKCD variants. All presented before the age of 2 years with fever and multi-organ involvement. Recurrent infections were common, with three patients developing BCGitis. All had high ANA, ds-DNA, and APL, with variable positivity for other autoantibodies. Complement studies revealed low C3/C4, and reduced C1q and CH50 in four patients. Treatment included corticosteroids and sequential immunosuppressive therapy, with five patients receiving biologic agents. While four achieved low disease activity on intensive treatment, three died due to severe disease and serious infections.ConclusionOur findings demonstrate that PRKCD deficiency is associated with autosomal recessive monogenic lupus, characterized by severe and potentially fatal outcomes. They also confirm the link with BCGitis susceptibility. The observed heterogeneity in disease course and treatment response highlights the need for precision medicine and warrants further investigation.