The proprotein convertase subtilisin/kexin 9 (PCSK9) protein is well known for its role in the regulation of plasma cholesterol levels. We previously showed that the initiation of hypercholesterolemia in nephrotic syndrome is related to PCSK9 secreted by the cortical collecting duct (CCD), whereas the established phase is due to PCSK9 secreted by the liver. In this study, we investigated whether early neutralization of circulating CCD-secreted PCSK9 could prevent sustained hypercholesterolemia. We showed that PAN rats, a widely used animal model that mimics nephrotic syndrome phenotype of human minimal change disease (MCD), developed increased levels of PCSK9 of CCD origin prior to peak proteinuria. CCD-secreted PCSK9 followed an increase in the transcription factor sterol regulatory element-binding protein 2 (SREBP2) expression, while both SREBP2 and PCSK9 were unmodified and reduced, respectively, in the liver. Treatment of PAN rats with anti-PCSK9 antibodies administrated at or shortly after the onset of proteinuria prevented the development of significant and sustained hypercholesterolemia through the course of PAN. These data confirm that PCSK9 secreted from the kidney initiates the development of hypercholesterolemia in MCD and suggest that early depletion of PCSK9 during the initial stages of MCD prevents sustained hypercholesterolemia.

IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is characterized by mesangial IgA deposition, which triggers complement activation, primarily through the alternative pathway. While complement dysregulation contributes to kidney injury and adverse outcomes, complement may also facilitate clearance of pathogenic immune complexes. Here, we compared complete complement component 3 (C3) deficiency with supplementation of complement factor H (Cfh), the principal regulator of alternative pathway, in murine IgAN models. C3 deficiency prevented complement activation but paradoxically increased glomerular IgA deposition and macrophage infiltration, resulting in complicated inflammatory response. In contrast, Cfh supplementation reduced glomerular IgA and C3 deposition, decreased inflammatory cytokine expression, attenuated macrophage infiltration, lessened glomerular area and ameliorated proteinuria while enhancing macrophage-mediated phagocytosis of circulating IgA immune complexes. Accordingly, IgAN patients with higher plasma CFH levels exhibited reduced mesangial IgA and C3 deposition alongside elevated circulating C3 levels, supporting CFH's protective role in regulating complement activation and promoting immune complex clearance. Our results reveal complement's dual role in IgAN: promoting inflammatory kidney injury while facilitating clearance of pathogenic IgA deposits. Targeted complement regulation via complement factor H supplementation, rather than complete complement inhibition via global complement component 3 knockout, achieves superior therapeutic effects by simultaneously controlling complement activation, enhancing immune complex clearance, suppressing inflammation, and reducing proteinuria. These findings identify complement factor H as a novel and promising therapeutic strategy for IgA nephropathy through targeted complement regulation.

Libman-Sacks endocarditis (LSE), characterized by sterile valvular vegetations, is a recognized complication of systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). However, its occurrence as the initial manifestation of previously undiagnosed autoimmune disease is uncommon and may create significant diagnostic uncertainty. A 27-year-old female presented to the emergency department with acute-onset exertional dyspnea, cough, and severe anemia, with a history of three consecutive first-trimester miscarriages. Initial evaluation revealed severe mitral regurgitation with valvular masses, raising suspicion for infective endocarditis. Further workup demonstrated elevated inflammatory markers, autoimmune hemolytic anemia, nephrotic-range proteinuria, and positive autoimmune serology, including antinuclear antibodies, anti-double-stranded DNA, anticardiolipin IgG, anti-β2-glycoprotein I IgG, and lupus anticoagulant. Transthoracic echocardiography showed severe mitral regurgitation with valvular masses and reduced left ventricular ejection fraction, while transesophageal echocardiography confirmed Libman-Sacks vegetations. Computed tomography of the chest revealed diffuse alveolar hemorrhage. The patient was diagnosed with new-onset SLE and APS, presenting with LSE and multisystem involvement. Management included pulse methylprednisolone therapy, hydroxychloroquine, cyclophosphamide, therapeutic anticoagulation, and plasma exchange for alveolar hemorrhage, resulting in clinical improvement with resolution of hemoptysis and improvement in cardiac function. This case is particularly notable because severe valvular disease led to the initial recognition of previously undiagnosed SLE and APS in the setting of simultaneous pulmonary, hematologic, renal, and obstetric manifestations. It highlights the importance of considering autoimmune etiologies in young patients with unexplained valvular heart disease, particularly in the presence of suggestive systemic features.

To investigate the influence of probiotic supplementation on parameters of renal function, dogs with chronic kidney disease (CKD) received a commercial probiotic formulation containing Enterococcus lactis SF68 (n = 8) or placebo (n = 8) for 60 days. Gut microbiome was investigated by comparing with healthy dogs (n = 10). Blood biochemistry, urinalysis, inflammatory and oxidative markers, uremic toxins and blood pressure were monitored. Higher presence of Lachnospiraceae family, Blautia bacterial species and Ruminococcus gnavus group was observed in dogs with CKD when compared with healthy dogs. Adding the probiotic to the diet decreased the abundance of Ruminococcus gnavus. Probiotic treatment resulted in a significant reduction in plasma concentrations of symmetric dimethylarginine (SDMA), from 1.50 ± 0.18 to 1.35 ± 0.16 µmol/l (p = 0.008), and indoxyl sulfate (IxS), from 19.1 ± 6.8 to 12.8 ± 4.8 µmol/l (p = 0.04). Cytokine inflammatory markers did not show significant changes. An increase in urine protein-to-creatine ratio, 1.5 ± 0.6 vs 1.2 ± 0.5, and in systolic blood pressure, 163 ± 11 vs 144 ± 6 mmHg (p = 0.033), was observed in the placebo group but not in dogs receiving probiotic. In conclusion, feeding Enterococcus lactis SF68 to dogs with CKD results in changes in intestinal microbiota that are associated with a decrease in plasma concentrations of IxS and SDMA and a reduction in proteinuria and systolic blood pressure.

The co-occurrence of rheumatoid arthritis (RA) and IgA nephropathy (IgAN) is rare, presenting diagnostic and therapeutic challenges, particularly regarding potential associations with therapies such as TNF inhibitors. We report the case of a 44-year-old man diagnosed with seronegative RA following evaluation for polyarthritis. His prior treatments included rituximab and etanercept, although specific details were unavailable. Adalimumab therapy, initiated in 2014, effectively controlled his RA symptoms for five years. However, in 2019, he developed progressive proteinuria (1 g/day), persistent microscopic hematuria, and low C3/C4 levels. A kidney biopsy revealed IgAN (Oxford classification M1, E0, S1, T1, C0). Suspecting a temporal association with adalimumab, the medication was discontinued, resulting in a significant decrease in proteinuria (to 0.1 g/day) and normalization of serum creatinine. Subsequent treatment with tofacitinib provided inadequate RA control. In 2021, certolizumab was initiated, leading to sustained improvement in RA symptoms (DAS28-CRP 2.6) and continued remission of IgAN (proteinuria 0.2 g/day). This case highlights the potential association between adalimumab use and the development of IgAN in patients with RA and underscores the importance of vigilant renal monitoring during TNF inhibitor therapy.

Amyloidosis is a rare, heterogeneous condition characterized by extracellular deposition of misfolded protein fibrils, resulting in organ dysfunction. Gastrointestinal amyloidosis (GIA), an uncommon manifestation, is often underdiagnosed due to its nonspecific symptoms, such as weight loss, abdominal pain, and diarrhea. Early recognition and accurate amyloid typing are crucial, as treatment strategies depend on the specific subtype involved. We report a case of a 42-year-old African male presenting with chronic epigastric pain, significant weight loss (BMI: 17.1), and a history of GERD. He had recently traveled to Equatorial Guinea. His symptoms, including nausea, decreased appetite, constipation, and persistent epigastric pain, were unresponsive to proton pump inhibitors. On examination, he was hypotensive and tachycardic. Laboratory workup revealed hyponatremia and elevated troponin T. Imaging showed fecal impaction and pyloric edema. Upper endoscopy and colonoscopy with biopsies confirmed amyloid deposition in the stomach, duodenum, ileum, and colon. Congo red staining demonstrated classic apple-green birefringence under polarized light. Cardiac evaluation revealed reduced global longitudinal strain. Serum studies showed elevated free lambda light chains and an IgG-lambda monoclonal band, while the urine protein/creatinine ratio was 361 mg/g, consistent with proteinuria. Chronic hepatitis B infection with detectable HBV DNA and elevated gamma/delta T cells on the lymphoma panel raised concerns for an underlying T-cell lymphoproliferative disorder. This case highlights the diagnostic complexity of gastrointestinal amyloidosis with multisystem involvement. The patient's presentation, along with elevated free light chains and monoclonal gammopathy, raised suspicion for AL amyloidosis, though chronic hepatitis B and possible lymphoproliferative disease kept AA amyloidosis in the differential. Consistent with the literature, vague gastrointestinal (GI) symptoms often delay diagnosis, underscoring the role of Congo red staining and mass spectrometry for confirmation and subtype identification. Recent trials support daratumumab for AL and patisiran/inotersen for ATTR amyloidosis. Early, accurate diagnosis is key to initiating appropriate therapy and improving outcomes, with multidisciplinary involvement crucial for optimal care.

Rituximab is an established therapy for primary membranous nephropathy, but anti-rituximab antibodies (ARA) have been associated with rituximab treatment failure. We report a 66-year-old woman with PLA2R-positive membranous nephropathy who developed ARA positivity and clinical features consistent with rituximab treatment failure, including B-cell reconstitution, undetectable serum rituximab levels, and worsening proteinuria despite declining anti-PLA2R antibody titers. Kidney biopsy confirmed stage III membranous nephropathy. She was subsequently treated with the humanized type II anti-CD20 antibody obinutuzumab, which induced complete depletion of circulating B cells, achieved therapeutic serum concentration, follow by both immunological and clinical remission within 8.5 months, despite persistent ARA positivity. This case suggests that obinutuzumab may be an effective rescue option after rituximab failure associated with ARA and underscores the importance of integrating therapeutic drug monitoring, ARA detection, and B-cell kinetics assessment in the management of refractory membranous nephropathy.

B-lymphocyte proliferative disorder have a certain incidence rate among the elderly. Whether these conditions require treatment is closely related to the presence of concurrent organ damage. This case report details the diagnostic journey and treatment process of a 76-year-old male patient who presented with nephrotic syndrome and acute kidney injury. His condition was further complicated by the presence of monoclonal M proteinemia and the malignant B-lymphocytes in the bone marrow. Through a series of examinations, a diagnosis of podocytopathy with suspected but unconfirmed B-cell lymphoproliferative disorder was established. Treatment involved with CD20 monoclonal antibody (Obinutuzumab). The patient achieved complete remission of proteinuria and normalization of renal function within one month, sustained at one-year follow-up. While the underlying mechanism remains uncertain, whether direct immunomodulation, B-cell clone control or both. This is the first reported case of successful treatment of podocytopathy with concurrent suspected but unconfirmed B-cell lymphoproliferative disorder using Obinutuzumab, offering a new therapeutic way for similar complex medical conditions.