Search Results (273)

Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA), remains a leading cause of skin and soft tissue infections (SSTIs) worldwide. Patients with renal edema, including those with nephrotic syndrome and chronic kidney disease (CKD), and critical illness, are particularly susceptible because of barrier dysfunction, immune impairment, and altered antimicrobial pharmacokinetics. This narrative review examines the mechanisms linking renal edema to increased susceptibility to cutaneous S. aureus infection and discusses their diagnostic and therapeutic implications. Three interconnected pathophysiological pathways appear central to this susceptibility: disruption of the cutaneous barrier, nephrotic and uremic immune dysfunction, and impaired lymphatic immune surveillance. These abnormalities facilitate bacterial colonization, and invasion, while S. aureus further exploits the renal host through adhesins, toxins, biofilm formation, and immune-evasion mechanisms. The review also highlights the challenges of managing severe staphylococcal infections in patients with kidney disease and critical illness, where augmented renal clearance, expanded volume of distribution, extracorporeal renal support, and fluctuating renal function may substantially influence antimicrobial exposure. Current management requires early recognition, source control, individualized antimicrobial selection, renal-adapted dosing, therapeutic drug monitoring, and antimicrobial stewardship. Although emerging anti-virulence and immunomodulatory strategies show promise, most remain at the preclinical or early translational stage. Overall, renal edema should be regarded as a biologically active modifier of host–pathogen interactions that contributes to increased susceptibility to cutaneous S. aureus infection across the spectrum of kidney disease. Full article

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome (NS). The remission rate of MN remains limited, and effective strategies for refractory MN are not established. We present the case of a 49-year-old Japanese woman with severe NS caused by MN. Kidney biopsy revealed glomerular basement membrane thickening with granular deposition of immunoglobulin G (IgG) and complement component 3. IgG subclass analysis showed predominant IgG1 deposition, with weak IgG2 and IgG3 deposition. Phospholipase A2 receptor (PLA2R) deposition was equivocal in the first kidney biopsy and negative in the second. Serum anti-PLA2R antibody was not detected. Electron microscopy revealed subepithelial, subendothelial, and mesangial electron-dense deposits. Detailed screening revealed no significant abnormalities other than appendiceal findings, suggesting secondary MN associated with appendiceal infection. Although combined therapy with prednisolone, cyclosporine, rituximab, and low-density lipoprotein apheresis was administered during the first 6 months, remission of MN was not achieved. During dialysis, initiated because of kidney failure, long-term multidisciplinary management, including control of appendiceal infection and inflammation and initiation of angiotensin II receptor blocker therapy, ultimately led to remission of MN and discontinuation of dialysis. Overall, even refractory MN requiring dialysis may have a reversible clinical course with careful conservative management and long-term follow-up. Full article

Daratumumab, a human IgG1 monoclonal antibody targeting CD38, is widely used in multiple myeloma and AL amyloidosis. Despite its clinical success, many patients fail to achieve durable responses or relapse, underscoring the importance of understanding resistance mechanisms. Drawing on experience from other better-studied monoclonal antibodies, resistance to daratumumab can be categorized into four main mechanisms: (1) reduced CD38 expression on plasma cells; (2) increased expression of complement inhibitory proteins (CD55/CD59), impairing complement-mediated cytotoxicity; (3) reduced drug bioavailability due to urinary loss in non-selective nephrotic syndrome; and (4) the development of neutralizing anti-daratumumab antibodies. Anti-drug antibodies (ADAs) may represent a potential mechanism of treatment failure through effects on pharmacokinetics, efficacy, and safety, even in patients on daratumumab therapy. Seven different trials have tested anti-daratumumab antibodies. Among them, anti-daratumumab antibodies were identified in only 0–2.4% of patients, and only in a small portion of these has it been proven to be neutralizing. Overall, ADAs appear rare, but these findings are likely underestimated due to short follow-up and suboptimal timing of assessment. In conclusion, standardized ADA monitoring, particularly months after treatment interruption or in cases of inadequate response or infusion-related reactions, may improve patient management and therapeutic outcomes. Full article

Background: Minimal change disease (MCD) is a leading cause of childhood nephrotic syndrome. Endoplasmic reticulum stress (ERS) and autophagy are implicated in its pathogenesis, but the precise mechanisms remain unclear. This study aimed to identify ERS and autophagy-related key genes (ERS-RGs and ARGs) in MCD using bioinformatic and experimental approaches. Methods: Transcriptomic data from GSE216841 and GSE246206 were analyzed. ERS-RGs and ARGs were obtained from prior literature. Candidate genes were selected by integrating weighted gene coexpression network analysis and differential expression analysis. Feature genes were identified via protein–protein interaction network analysis and machine learning (Least Absolute Shrinkage and Selection Operator and Boruta). Key genes were validated by expression analysis and receiver operating characteristic evaluation. A multilayer perceptron (MLP) model was constructed, and regulatory networks, immune infiltration, and chemical compound prediction were analyzed. The expression levels of the identified key genes were preliminarily assessed in peripheral blood samples using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results: LIG4 and ZRANB3 were identified as key genes, both significantly downregulated in the MCD group, and the gene-based MLP model effectively predicted MCD probability. Overall, 13 significantly different immune cell types (e.g., CD56⁺ natural killer and activated dendritic cells) were detected. Regulatory networks (transcription factor-messenger RNA (mRNA) and long non-coding RNA-microRNA-mRNA) and 8 common chemical compounds (e.g., bisphenol A, acetaminophen) targeting these genes were predicted. Notably, peripheral blood RT-qPCR analysis revealed significant LIG4 and ZRANB3 downregulation, suggesting a systemic expression signature. Conclusion: LIG4 and ZRANB3 are key genes associated with ERS and autophagy in MCD, providing insights for diagnosis and targeted therapy. Full article

Membranous nephropathy (MN) and minimal change disease (MCD) are the most common causes of nephrotic syndrome following hematopoietic stem cell transplantation (HSCT), a complication conventionally attributed to chronic graft-versus-host disease (GVHD). Paraneoplastic MCD is well described in lymphoid malignancies but is rarely reported in myeloid neoplasms. We report two cases of biopsy-confirmed MCD presenting as the initial manifestation of acute myeloid leukemia (AML) relapse following allogeneic HSCT. Both patients were White men in their sixties with relapsed/refractory AML who developed nephrotic-range proteinuria and acute kidney injury after matched unrelated donor HSCT without histologic evidence of GVHD. Renal biopsies confirmed MCD in both cases. Corticosteroid therapy was ineffective in halting renal deterioration; renal function improved only after initiation of leukemia-directed therapy, with one patient achieving dialysis independence. These cases highlight a rare paraneoplastic presentation of AML relapse. Nephrotic syndrome due to MCD may signal post-HSCT leukemia recurrence, and evaluation for AML relapse warrants consideration in steroid-refractory cases or those without concurrent GVHD. In such cases, control of the underlying malignancy, rather than escalation of immunosuppression, may be central to renal recovery. Full article

Renal venous thrombosis (RVT) is a location of unusual-site venous thromboembolism. RVT occurs more commonly in males, and shows a bimodal age distribution, with a neonatal and adult peak. Abdominal malignancies and nephrotic syndrome are prominent risk factors in adults, whereas hypotension, birth asphyxia, sepsis, umbilical venous catheters and prematurity are the predominant causes in children. The most common symptoms of RVT include abdominal pain and macroscopic haematuria. A palpable abdominal mass is often observed in neonates, while antenatal RVT may present with signs of foetal distress. Bilateral RVT can lead to acute renal failure. Anticoagulation is the cornerstone of treatment, traditionally with unfractionated heparin, low molecular weight heparin and vitamin K antagonists, although recent evidence is emerging on the use of the direct oral anticoagulants in selected RVT patients. Endovascular procedures (e.g., local thrombolysis or mechanical thrombectomy) are usually reserved for more severe cases, such as bilateral acute RVT causing kidney dysfunction. Outcome data show variability in mortality rates, with some adult cohorts reporting high mortality linked to underlying malignancies and other comorbidities. In paediatric cohorts, mortality is low, but RVT can lead to long-term complications, including kidney atrophy, kidney dysfunction and hypertension. This narrative review aims to synthesise the current evidence on RVT, with a particular focus on anticoagulant prophylaxis and treatment, and clinical outcomes in adult and paediatric populations. Full article

Background and Objectives: To investigate prognostic risk factors and determine the incidence, clinical characteristics, and predictors of heart failure (HF) development in pediatric patients with end-stage kidney disease (ESKD) secondary to steroid-resistant nephrotic syndrome (SRNS). Materials and Methods: We conducted a retrospective cohort study of pediatric patients diagnosed with ESKD secondary to nephrotic syndrome (NS) between 2014 and 2020. Patients were stratified based on clinical outcomes and the occurrence of HF during follow-up. Comparative analyses of clinical characteristics, laboratory parameters, and cardiac assessments were performed across groups. Multivariate logistic regression was used to identify independent risk factors for HF development within the first year and for adverse prognosis at five years. Results: The cohort comprised 172 children with ESKD secondary to NS. Multivariate logistic regression identified HF as an independent risk factor for adverse long-term outcomes in pediatric patients with ESKD. During follow-up, HF developed in 27 patients (15.7%) within the first year after ESKD diagnosis, and in 45 patients (26.2%) by the end of five years. Early HF onset (within the first year) was associated with a significantly reduced five-year survival rate. Independent risk factors for HF development included elevated cardiac troponin I levels (OR = 6.786, 95% CI: 2.326–19.799), a history of cardiac arrhythmias (OR = 2.951, 95% CI: 1.260–6.912), and the presence of left heart enlargement (OR = 23.669, 95% CI: 2.876–194.827), and valvular regurgitation at the initial post-ESKD diagnosis evaluation. Conclusions: HF is associated with markedly reduced survival. Crucially, our findings demonstrate that pre-existing cardiovascular structural abnormalities—specifically left heart enlargement—and elevated cTnI are robust, early predictors of HF. These findings necessitate a paradigm shift in pediatric ESKD management, we advocate for the implementation of systematic baseline echocardiographic and biomarker screening at the immediate onset of ESKD. Identifying these subclinical, yet modifiable, structural changes provide a critical therapeutic window for targeted anti-remodeling interventions to significantly improve long-term prognosis. Full article

Background: Septic Charcot neuroarthropathy is a limb- and life-threatening condition characterized by the coexistence of neuropathic joint destruction and infection. In patients with severe systemic compromise, major amputation is often considered inevitable. Case Presentation: A 47-year-old man with untreated diabetes mellitus presented with progressive painless swelling of the left foot. He had morbid obesity (120 kg, 165 cm; body mass index 44.1 kg/m²), severe hypoalbuminemia, and chronic kidney disease associated with nephrotic syndrome. Laboratory tests showed marked inflammation and poor glycemic control, and blood cultures were positive for methicillin-resistant Staphylococcus aureus (MRSA). Radiographs and computed tomography demonstrated destructive changes involving the talonavicular and subtalar joints, consistent with septic Charcot neuroarthropathy involving the midfoot. Because of sepsis, pulmonary edema, and heart failure, below-knee amputation was proposed at the referring hospital. However, limb salvage was attempted using aggressive debridement, continuous local antibiotic perfusion (CLAP; gentamicin 1200 μg/mL) administered for 14 days, and temporary circular external fixation. Serum gentamicin concentrations and renal function were regularly monitored to ensure systemic safety and avoid nephrotoxicity. Results: Repeat irrigation and final debridement were performed 20 days after the index surgery, at which time the external fixator was removed and intraoperative cultures were negative. The patient was discharged 2 months after surgery without evidence of recurrent infection. At 4-year follow-up, no recurrence had occurred, and the patient was able to walk independently. Conclusions: Limb salvage may be feasible even in severely compromised patients with septic Charcot midfoot and MRSA bacteremia when aggressive debridement, CLAP, and temporary external fixation are combined with careful systemic safety monitoring. This case suggests that limb salvage may be considered in selected high-risk patients, although further studies are required. Full article

Background: Steroid resistance indicates poor prognosis in pediatric nephrotic syndrome, but predictive models and risk factors for steroid-resistant nephrotic syndrome (SRNS) remain poorly understood. Methods: We searched PubMed, Embase, Scopus, CNKI, SinoMed, Wanfang, and VIP (inception to 1 March 2025) for studies developing SRNS prediction models or identifying risk factors. Odds ratios and AUC were pooled using random-effects meta-analysis. Risk of bias was assessed with PROBAST and Newcastle-Ottawa Scale. Results: Out of 2264 studies, 23 were included. Prediction models were mainly developed using logistic regression (16/17, 94.1%). The most frequently reported predictors included erythrocyte sedimentation rate and vitamin D binding protein. The reported AUC ranged from 0.75 to 0.88. Only one model had undergone external validation with an accuracy of 0.94. A total of 22 independent risk factors were identified, five of which—low birth weight, decreased urine output, hypertension, serum albumin, and serum IgM—were not in existing models. In total, 76% of model studies and 26% of risk factor analyses were at high or moderate risk of bias. Conclusions: Existing SRNS prediction models reported apparent discrimination but had a high risk of bias and very limited external validation, which substantially restricts their current clinical applicability. Several relevant risk factors remain unincorporated. Future research should prioritize rigorous model development and multi-center external validation. Full article

Introduction: Steroid-resistant nephrotic syndrome (SRNS) represents a severe and challenging form of pediatric nephrotic syndrome and is associated with a high risk of progression to end-stage kidney disease. Calcineurin inhibitors (CNIs) are the standard second-line therapy; however, their use is limited by frequent relapses and long-term nephrotoxicity. Mycophenolate mofetil (MMF) offers a more favorable safety profile and a complementary mechanism of action; however, the clinical utility of combining MMF with CNIs remains largely under-explored in this population. Case Presentation: We describe a series of nine pediatric patients with steroid-resistant or steroid-dependent nephrotic syndrome who were refractory to cyclosporine monotherapy. These patients were treated with a combination regimen of cyclosporine (4–5 mg/kg/day; target trough levels of 75–150 ng/mL) and MMF (600 mg/m²/day). This therapeutic approach was associated with a reduction in corticosteroid dosage and a decrease in the annual number of relapses in most patients. Conclusions: In this small case series of pediatric patients with corticosteroid-dependent or steroid-resistant nephrotic syndrome refractory to cyclosporine monotherapy, the addition of mycophenolate mofetil was associated with a reduction in relapse frequency and corticosteroid requirements. Despite the limited sample size, these findings suggest that combination therapy may be a therapeutic option in difficult-to-treat pediatric nephrotic syndrome and warrant further evaluation in controlled studies. Full article

Background/Objectives: AA amyloidosis is a serious complication of chronic inflammation, which may arise in the setting of inborn errors of immunity (IEIs) due to recurrent or persistent infections. Common variable immunodeficiency (CVID) is the most frequent symptomatic IEI in adults, yet its association with secondary AA amyloidosis remains rarely reported. Case presentation: We describe a 37-year-old male with a history of recurrent pneumonia, chronic sinusitis, and osteomyelitis with sepsis since childhood. At age 33, he developed bilateral pneumonia after COVID-19, followed by repeated lower respiratory tract infections. At age 36, nephrotic syndrome (proteinuria 10.69 g/day, hypoalbuminemia) led to kidney and gastric mucosa biopsies, which confirmed AA amyloidosis. Immunological workup revealed panhypogammaglobulinemia (IgG 0.1 g/L, IgA 0.01 g/L, IgM 0.28 g/L), markedly reduced switched memory B cells, and an inverted CD4⁺/CD8⁺ ratio. Chest CT showed bronchiectasis, bronchiolitis, and mediastinal lymphadenopathy. Whole-exome sequencing excluded known monogenic IEIs, autoinflammatory, or hereditary amyloidosis genes; a heterozygous likely pathogenic variant in ODAD2 (associated with primary ciliary dyskinesia) was considered incidental. A diagnosis of CVID with secondary AA amyloidosis was established. Conclusions: This case illustrates that CVID may remain undiagnosed for decades and present with secondary AA amyloidosis as the first major complication. In any patient with nephrotic syndrome and a history of recurrent or unusual infections, an IEI should be actively excluded. Early recognition of CVID and appropriate immunoglobulin replacement therapy can prevent infectious exacerbations and potentially halt amyloid progression. Full article

Background: Acute kidney injury (AKI) is a common and serious complication in patients with liver cirrhosis and is associated with poor outcomes. However, whether the association between nephrotic-range proteinuria (NRP) and severe AKI varies by liver disease severity remains unclear. Methods: This retrospective cohort study included 408 adult patients with cirrhosis stratified by Child–Pugh class (A, B, and C). Severe AKI was defined as Kidney Disease: Improving Global Outcomes stage 2–3. Multivariable logistic regression analyses were performed in the overall cohort and within each class, with the additional evaluation of interaction effects. Results: The incidence of severe AKI increased from 18.4% in class A to 38.8% in class C. In the extended multivariable model incorporating hemodynamic and inflammatory variables, nephrotic-range proteinuria was not significantly associated with severe AKI. In stratified analyses, a significant association was observed only in Child–Pugh class A. Additional analyses suggested that this relationship was attenuated after accounting for sepsis and systemic severity. Conclusions: Although NRP prevalence was similar across Child–Pugh classes, the association between NRP and severe AKI appeared to vary by disease stage, particularly before adjustment for systemic severity. Full article

Steroid-resistant nephrotic syndrome (SRNS) in childhood frequently reflects monogenic podocytopathies in which immunosuppression is ineffective. Biallelic variants in MYO1E, encoding the class I myosin Myo1E, cause a distinctive form of focal segmental glomerulosclerosis (FSGS) often accompanied by “Alport-like” multilamination of the glomerular basement membrane (GBM). Early recognition has therapeutic and prognostic implications. A previously healthy 4-year-old boy presented with generalized edema and nephrotic-range proteinuria. Glucocorticoids induced no remission; sequential calcineurin inhibition (cyclosporine, then tacrolimus) and a single dose of ofatumumab yielded only transient, partial reductions in proteinuria. A first biopsy elsewhere showed FSGS with nonspecific IgM/C3 trapping; electron microscopy (EM) was not performed. At age 10, repeat biopsy with EM revealed ~30% segmental foot-process effacement, focal GBM thickening (to 1740 nm), irregular lamina densa multilamination, and lamellar duplications without immune-complex deposits—features highly suggestive of hereditary GBM disease. Targeted sequencing identified compound-heterozygous MYO1E variants segregating in trans: a canonical splice-donor change (c.2785+1G>A) and a frameshift (c.3094_3097del; p.Thr1032Profs*73). Each parent was an unaffected heterozygous carrier; the sibling was negative. Supportive therapy with ramipril was continued. At last follow-up (January 2025), renal function was normal (serum creatinine 0.5 mg/dL; creatinine clearance 122 mL/min) with stable sub-nephrotic proteinuria (0.52 g/day; 16 mg/m² per hour) and normotension. This case broadens clinicopathologic recognition of MYO1E-associated nephropathy and highlights the teaching point that Alport-like GBM changes are not pathognomonic for type IV collagen disorders but may signal defects in podocyte cytoskeletal anchoring. Full article

Background/Objectives: Differentiating minimal change disease (MCD) from focal segmental glomerulosclerosis (FSGS) remains a diagnostic challenge. We hypothesised that differences in glomerular protein selectivity could translate into distinct serum protein electrophoresis (SPEP) profiles, particularly in severe nephrotic syndrome. Methods: We retrospectively analysed SPEP profiles of adults with biopsy-proven MCD (n = 27), primary FSGS (n = 27), and secondary FSGS (n = 20). Diagnoses were established according to KDIGO guidelines and the Mayo Clinic classification. A severe subgroup was defined by a relative albumin fraction <40% to evaluate patterns in marked hypoalbuminaemia. Results: Secondary FSGS demonstrated significantly higher albumin-to-globulin (A/G) ratios compared with immune-mediated podocytopathies (MCD and primary FSGS), yielding excellent discrimination (AUC > 0.98). In contrast, discriminatory performance between MCD and primary FSGS in the overall cohort was limited (AUC = 0.657). However, within the severe subgroup, the A/G ratio provided clinically meaningful separation (AUC = 0.787). An A/G ratio > 0.49 identified primary FSGS with 86.7% sensitivity and 81.2% specificity. Correlation analysis revealed a strong inverse association between albumin and α2-globulin fractions in immune-mediated podocytopathies (ρ < −0.8), whereas this relationship was attenuated in secondary FSGS (ρ = −0.57). Conclusions: The A/G ratio may represent a practical adjunctive biomarker in the evaluation of podocytopathies. Values > 1.0 strongly favour secondary FSGS, while markedly reduced ratios in severe nephrosis are characteristic of MCD. These findings suggest that differences in glomerular selectivity and the hepatic compensatory response are reflected in routine electrophoretic profiles. Full article

To clarify the genetic classification, diagnostic strategies, and precision treatment pathways of steroid-resistant nephrotic syndrome (SRNS), this review systematically reviews the genetic stratification system of SRNS by integrating recent advances in genetic testing technologies and pathogenesis research. It contains the pathogenic mechanisms, diagnostic protocols, and therapeutic correlations of different genetic subtypes, while summarizing current progress and clinical challenges in gene therapy. Results indicate SRNS can be categorized into genetic (38–58%) and non-genetic/immune-mediated (40–60%). A stepwise diagnostic system comprising core proteinuria gene panel testing, whole-genome sequencing (WGS), whole-exome sequencing (WES), and supplementary multi-omics/long-range sequencing is proposed, suited for populations with “typical phenotypes and moderate genetic risk”, “atypical phenotypes and high genetic suspicion”, and “complex structural/non-coding region variants” respectively. Pathogenic mechanisms directly determine therapeutic strategies: COQ2/PDSS2 mutations respond to coenzyme Q10 suplementation, while NPHS1 mutations necessitate early renal transplantation. Adeno-associated virus (AAV)-mediated gene therapy and CRISPR-Cas editing show preclinical promise but face challenges including incomplete detection coverage and clinical translation difficulties. Genetic technologies are driving SRNS management transformation from “empirical treatment” to “mechanism-oriented precision diagnosis and therapy”. Future efforts should focus on overcoming genetic testing limitations and gene therapy translation bottlenecks to enhance diagnostic and therapeutic efficacy. Full article