BACKGROUND:Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a rare renal disorder for which prospective controlled treatment evidence is limited. Clone-directed therapies targeting plasma cells or B cells are increasingly used, but comparative prospective data are lacking. METHODS:This single-center, open-label, pilot RCT aimed to evaluate the feasibility and preliminary efficacy of plasma cell-targeted therapy (bortezomib-cyclophosphamide-dexamethasone, BCD) versus B-cell-targeted therapy (rituximab, RTX). Twenty eligible patients were randomized (1:1) to receive either 6 cycles of BCD or 4 weekly doses of rituximab at375 mg/m². In patients with B-cell reconstitution > 5/μL, a 500 mg rituximab booster dose was administered at 6 months according to the prespecified protocol. The primary efficacy endpoint was overall renal response at 12 months. Changes in proteinuria, serum albumin and estimated glomerular filtration rate were also assessed at 6 and 12 months as secondary outcomes. Safety outcomes included infections and hematologic toxicity. RESULTS:Baseline characteristics were generally comparable between groups. The median age was 57 years, and mean proteinuria 4.1 ± 3.1 g/d. In the primary intention-to-treat analysis (n = 20), the primary outcome of overall renal response at 12 months was observed in 60% (6/10) of patients in the BCD group and 70% (7/10) in the RTX group (P = 1.0). Treatment failure occurred in 2 patients in the BCD group and none in the RTX group. At 6 months, complete response occurred in five patients in the BCD group and three patients in the RTX group. Both groups showed reductions in proteinuria and improvements in serum albumin over 12 months. A transient decline in estimated glomerular filtration rate was observed in the BCD group at 6 months and recovered by 12 months. Safety profiles were manageable, with one serious adverse event, pneumonia, in the BCD group. CONCLUSION:Both BCD and rituximab were associated with renal responses in this exploratory pilot trial of PGNMID. Given the small sample size, open-label design, and differences in treatment exposure structure, these findings are hypothesis-generating. Larger multicenter studies with longer follow-up are needed to define optimal therapy for PGNMID.Trial registration: chictr.org.cn Identifier: ChiCTR2500102928.

Introduction: Light chain cast nephropathy (LCCN) results from the coprecipitation of monoclonal light chains with Tamm-Horsfall protein (THP) within the distal nephron, which forms obstructive casts. Although previous studies have suggested that crystalline LCCN variants may develop independently of THP, the role of THP in classic LCCN remains unclear. We investigated THP involvement in diverse LCCN variants and compared the clinicopathological profiles and outcomes of THP-positive and THP-negative cohorts. Methods: We retrospectively analyzed 32 patients with newly diagnosed multiple myeloma and biopsy-proven LCCN. Cases were classified as THP-positive (n = 19) or THP-negative (n = 13) based on THP immunohistochemical staining. Clinical, laboratory, and histopathological data were compared and supplemented by a proteomic analysis of cast composition using laser microdissection coupled with liquid chromatography-tandem mass spectrometry. Results: Immunoreactive-negative THP LCCN, accounting for 40.6% (13/32) of the cohort, presented with significantly lower hemoglobin, higher serum creatinine, more frequent acute kidney injury (AKI), and greater dialysis dependence than their THP-immunoreactive-positive counterparts. Immunoreactive-negative THP patients exhibited exacerbated tubular atrophy, interstitial inflammation, and acute tubular injury. Mass spectrometry further confirmed that THP was undetectable in a portion of immunoreactive-negative THP casts. No significant between-group difference was observed in survival. Conclusion: Immunoreactive-negative THP LCCN correlates with severe anemia, AKI requiring dialysis, and marked tubular damage. Therefore, immunohistochemical staining for THP should be carefully evaluated in patients with LCCN. Further exploration of the mechanisms underlying LCCN pathogenesis is warranted.

Acute kidney injury (AKI) represents a life-threatening condition among hospitalized patients, where early prediction enables prevention. Despite advances in existing models, clinical implementation remains hindered by excessive false positive rates (70%-94%) and lack of actionable clinical insights. We conduct a multi-center retrospective cohort study and develop a two-model large language model framework: AKI-PM (Prediction Model) for predicting AKI occurrence within 24 hours and AKI-RAM (Risk Attribution Model) for providing explainable risk attribution. Using a cohort of 140,637 hospital admissions across four geographically diverse Chinese hospitals, we demonstrate that AKI-PM achieves high predictive performance in internal validation (area under curve 0.95, positive predictive value 0.68) and maintains robust generalizability across external sites after few-shot (area under curve 0.92-0.96, positive predictive value 0.69-0.74). Crucially, AKI-RAM provides structured, clinically actionable risk explanations by distinguishing modifiable from non-modifiable factors and offering tailored recommendations. In a clinical evaluation of 200 cases from four independent hospitals by six nephrologists, AKI-RAM receives high scores across eight dimensions (Likert scale: 4.18-4.88) with moderate to good inter-rater reliability (intraclass correlation coefficients: 0.680-0.803). This integrated framework addresses critical limitations in AI-driven clinical prediction by combining accuracy with interpretability, offering a scalable solution for early AKI prevention in diverse healthcare settings.

BACKGROUND:The association between immunoglobulin light chain variable (IGVL) gene usage and clinicopathological features in renal AL amyloidosis requires further research. This study analyzed IGVL genes and their associations with clinicopathological characteristics, organ involvement and survival outcomes in a Chinese cohort. METHODS:We retrospectively enrolled 273 renal AL amyloidosis patients. Amyloid deposits were microdissected and subjected to mass spectrometry (MS)-based proteomics to identify IGVL genes. Clinicopathological features, organ involvement and survival data were systematically analyzed. RESULTS:IGVL genes were successfully identified in 250 patients (92%). IGLV6-57 (32%) was predominant, IGKV1 family (12%) was the most prevalent in AL-κ cases. IGLV6-57 was associated with a higher rate of full nephrotic syndrome, while was linked to milder vascular amyloid deposition and total amyloid deposition. IGKV1 was associated with heavier amyloid burden, severe interstitial inflammation and a higher rate of hepatic involvement, IGLV6-57 was correlated with reduced hepatic involvement. IGLV1-51 potentially predicted rapid renal progression and dialysis risk. CONCLUSION:The IGVL gene usage is associated with distinct clinicopathological features in renal AL amyloidosis, IGLV6-57 is linked to a higher frequency of full nephrotic syndrome, IGKV1 is associated with severe kidney structural damage and hepatic tropism, and IGLV1-51 potentially predicts poor renal survival.

Light chain proximal tubulopathy (LCPT) is a rare kidney disorder associated with monoclonal gammopathy, traditionally defined by crystalline inclusions in proximal tubular epithelial cells. A poorly recognized variant, fibrillary LCPT, is characterized by large nonamyloid fibrillar aggregates but has remained inconsistently classified, leading to diagnostic uncertainty. We aimed to clarify its clinicopathologic features and refine its position within the LCPT spectrum. We retrospectively analyzed 41 biopsy-proven LCPT cases, reclassified by ultrastructural features into crystalline LCPT (n = 22), fibrillary LCPT (n = 11), amyloid LCPT (n = 2), and LCPT with lysosomal indigestion (n = 6). Fibrillary LCPT showed irregular cytoplasmic fibrils measuring 6 to 18 nm in diameter, arranged in intersecting, fishbone-like, or compact bundle-like patterns, confined to proximal tubular epithelial cells. These fibrils were Congo red negative and not apparent on light microscopy. Conventional immunofluorescence (IF) on frozen tissue was uniformly negative in fibrillary LCPT, and pronase-digested paraffin IF detected κ restriction in only 7 of 11 cases; immunoelectron microscopy confirmed κ light chain labeling in all paraffin IF-negative cases, yielding 100% diagnostic sensitivity. Clinically, most fibrillary LCPT cases were associated with monoclonal gammopathy of renal significance (72.7%), with the remainder linked to multiple myeloma (27.3%). This subtype was commonly associated with Fanconi syndrome and reduced estimated glomerular filtration rate, with a subset of cases developing acute kidney injury. Following clone-directed therapy, a majority of patients achieved stable renal function, and 85% showed improvement in tubular dysfunction, although proteinuria reduction was less pronounced than in crystalline LCPT. Fibrillary LCPT represents a distinct, nonamyloid entity characterized by Congo red-negative fibrils, κ light chain restriction, and frequent association with Fanconi syndrome and monoclonal gammopathy of renal significance. We propose a refined 4-tier ultrastructural classification comprising 4 LCPT subtypes (crystalline LCPT, fibrillary LCPT, amyloid LCPT, and LCPT with lysosomal indigestion) to improve diagnostic precision and guide management.

This retrospective single-center cohort included 480 immunoglobulin light-chain amyloidosis (AL) and 61 light chain deposition disease (LCDD) patients from Peking University First Hospital to compare clinical profiles and outcomes. AL frequently presented with multisystem (≥ 3 organs, 31.0%) and cardiac involvement (60.8%). LCDD was kidney-dominant (eGFR < 50 mL/min/1.73m², 85.2%) with higher clonal burden (dFLC > 180mg/L, 44/60 [73.3%] with available data), a trend toward higher CR rate (65.8% vs 48.8% AL, P = 0.058), and 100% ≥ PR to daratumumab in a small subgroup (n = 11). PI-based therapy was the main backbone (66.3% vs 66.0%). LCDD had superior OS ( P < 0.001), while AL showed better renal survival in high-risk strata (albumin < 30g/L, eGFR < 50, 24h-UTP > 5g; all P < 0.05). These findings support disease-specific management: deep hematologic remission for AL and renal protection plus clone-directed therapy for LCDD.

Introduction:It has been recognized that periodic acid-Schiff (PAS) staining of amyloid deposits is typically weak or negative in the majority of AL amyloidosis. However, a subset of patients exhibits PAS-positive deposits, and their clinicopathological significance remains unclear. Methods:We retrospectively analyzed 269 patients with renal biopsy-proven AL amyloidosis from our institution; 72 were classified as PAS positive and 197 as PAS negative. Baseline demographics, clinical data, renal pathology features, treatment strategies, and prognostic information were collected. Multivariable linear regression and Cox proportional hazards models were used to determine the impact of PAS-positive amyloid deposition on renal function and patients' outcomes. Results:Compared with the PAS-negative group, PAS-positive patients had higher serum creatinine (94.40 vs. 79 μmol/L, p = 0.005) and increased renal insufficiency ratio (31.94% vs. 14.72%, p = 0.002). Histopathology showed more severe glomerular and interstitial amyloid deposition (p = 0.037, p = 0.049, respectively). In multivariable linear regression, PAS-positive deposits (β = 0.158, p = 0.005) were independently associated with higher serum creatinine. PAS-positive patients showed significantly worse renal survival (HR: 3.05, 95% CI: 1.40-6.65, p = 0.005), independent of age, treatment regimens, renal stage, and pathological cores. Meanwhile, PAS-positive staining was an adverse prognostic factor (HR: 2.34, 95% CI: 1.24-4.43, p = 0.009) for overall survival after adjusting for AL type, age, treatment, organ involvement, interstitial fibrosis and tubular atrophy, and total amyloid burden. Conclusion:PAS-positive amyloid deposits are associated with more severe renal injury and poorer prognosis in AL amyloidosis.

BACKGROUND:Whether fractional flow reserve (FFR)-guided revascularization improves outcomes in atherosclerotic renal artery stenosis (ARAS) remains uncertain. OBJECTIVES:This study will evaluate whether the benefit of FFR-guided stenting sustained at 1 year including renal outcomes. METHODS:FAIR pilot is an investigator-initiated, multicentre, open-label trial with blinded endpoint adjudication. Adults with ARAS were randomized 1:1 to FFR-guided vs angiography-guided groups. Stenting was performed in the FFR-guided group when FFR <0.80, and it was performed for all in the angiography-guided group regardless of FFR. The percentage changes in ambulatory daytime mean systolic blood pressure (DMSBP), composite index of antihypertensive medicines (CIAHM), and renal outcomes were analyzed for 1 year. RESULTS:Among all 107 randomized patients, 1-year follow-up was achieved in 50 (93%) in the FFR-guided group and 51 (96%) in the angiography-guided group. At 1 year, DMSBP, CIAHM, and renal outcomes were similar between the groups, while stenting rate was lower with FFR guidance (46% vs 100%, P < 0.01). Patients with FFR <0.80 who underwent stenting experienced the greatest blood pressure reductions (median [IQR] ΔDMSBP: 13 [4, 21] mm Hg at 3 months; 8 [3, 16] mm Hg at 6 months, 7 [0, 16] mm Hg at 12 months; all paired P < 0.05) and sustained declines in CIAHM (2 [0, 5] at 3, 6, and 12 months; all paired P < 0.05). Significant 12-month estimated glomerular filtration rate improvement after stenting was only observed when FFR <0.80, with greater percentage eGFR improvement under quantile regression analysis. CONCLUSIONS:At the 1-year follow-up, FFR-guided renal artery stenting reduced stent use without loss of blood pressure control or renal safety compared with angiography guidance.

Background: It has been recognized that Periodic acid–Schiff (PAS) staining of amyloid deposits reveals weak or negative in the majority of AL amyloidosis. However, a subset of patients exhibits PAS-positive deposits, and their clinicopathological significance remains unclear. Methods: We retrospectively analyzed 269 patients with renal biopsy-proven AL amyloidosis from our institution; 72 were classified as PAS-positive and 197 as PAS-negative. Baseline demographics, clinical data, renal pathology features, treatment strategies, and prognostic information were collected. Multivariable linear regression and Cox proportional hazards models were used to determine the impact of PAS-positive amyloid deposition on renal function and patients’ outcomes. Results: Compared with the PAS-negative group, PAS-positive patients had higher serum creatinine (94.40 vs. 79 μmol/L, P = 0.005) and increased renal insufficiency ratio (31.94 % vs. 14.72%, P = 0.002). Histopathology showed more severe glomerular and interstitial amyloid deposition (P = 0.037, P = 0.049, respectively). In multivariable linear regression, PAS-positive deposits (β = 0.158, P = 0.005) were independently associated with higher serum creatinine. PAS-positive patients showed significantly worse renal survival (HR 3.05, 95% CI: 1.40 – 6.65, P = 0.005), independent of age, treatment regimens, renal stage, and pathological cores. Meanwhile, PAS-positive staining was an adverse prognostic factor (HR 2.34, 95% CI: 1.24 – 4.43, P = 0.009) for overall survival after adjusting for AL-type, age, treatment, organ involvement, interstitial fibrosis and tubular atrophy, and total amyloid burden. Conclusion: PAS-positive amyloid deposits are associated with more severe renal injury and poorer prognosis in AL amyloidosis.

CASE PRESENTATION:A 50-year-old woman was admitted to our hospital with a 2-year history of productive cough and intermittent low-grade fever, which had shown only temporary improvement with short courses of antibiotics. Her past medical history was notable for hysteromyoma, treated with hysterectomy 6 years earlier. She did not smoke, did not report any occupational chemical exposures, and reported a family history of cor pulmonale in her father. Approximately 2 years before admission, a thoracic CT scan at a local hospital revealed diffuse cystic lesions with scattered bilateral nodules and calcifications. Bronchoscopy with bronchoalveolar lavage and transbronchial lung biopsy at that time demonstrated scattered inflammatory cells in the interstitium, but did not yield a definitive diagnosis. Subsequently, she was managed symptomatically with close monitoring. One year before admission, her serum creatinine level began to rise from normal levels, eventually peaking at 5.21 mg/dL and accompanied by renal hypertension. A renal biopsy at the same institution suggested acute interstitial nephritis, for which she received a 3-month course of methylprednisolone (initial dose, 40 mg). Unfortunately, neither her chest imaging results nor renal function improved.

Monoclonal free light chains drive diverse renal pathologies in plasma cell dyscrasias. However, the mechanism of light chain proximal tubulopathy remains poorly understood because sequence data are scarce. Here we characterize full-length kappa free light chains from five patients with light chain proximal tubulopathy, four of whom had intracellular crystals. All showed the highest homology to the IGKV1-33 germline, while crystal-forming light chains contained distinct single-residue substitutions. These light chains generated a stable ~12-kDa fragment resistant to digestion by cathepsin B and D, a pattern not observed in non-crystal-forming light chains. Mechanistically, a single-residue substitution contributed substantially to cathepsin D resistance and stable fragment formation. In vivo comparison of recombinant κWJJ and its single-amino acid mutant further supported an important role for this substitution in intracellular crystal formation. These findings establish a sequence-based link between impaired lysosomal processing and crystal accumulation in light chain proximal tubulopathy.

The aim of this study is to explore the quantity profiles of amyloid signature proteins (serum amyloid P component, SAP; apolipoprotein E, ApoE; apolipoprotein A-IV) in common types of renal amyloidosis by mass spectrometry and immunostaining methods. Twenty-one patients with renal amyloidosis of different types evaluated at the Renal Pathological Center of Peking University First Hospital from 2000 to 2021 were enrolled. Immunohistochemistry (IHC) and laser microdissection combining with mass spectrometry (LMD-MS) were applied to investigate the localization and quantity profiles of signature proteins in renal amyloidosis. The co-localization relationships among signature proteins and amyloid fibrils, as well as the ultrastructural localization of SAP were examined by laser scanning confocal microscopy (LSCM) and immuno-electron microscopy (IEM), respectively. By MS-based proteomic analysis, large spectra numbers of ApoE and its higher abundance were noted in four types of amyloidosis when compared with SAP, and ApoA-IV was absent in ALECT2 amyloidosis. LSCM showed ApoE and SAP co-localized with amyloid fibrils in renal AL-κ, AL-λ and ALECT2 amyloidosis. ApoA-IV co-localized with amyloid fibrils in AL-κ and AL-λ amyloidosis, but was not found in ALECT2 amyloidosis. By semi-quantitative analysis based on LSCM and IEM, the quantity levels of signature proteins in AL-κ appeared to be lower than that in AL-λ (P < 0.05) or ALECT2 (P < 0.05), while there was no significant difference between AL-λ and ALECT2 amyloidosis. Both of SAP and ApoE were the ubiquitous signature components of renal amyloidosis (AL, AA, ALECT2), as well as ApoA-IV in AL and AA, but not in ALECT2. ApoE was the key signature protein in renal amyloidosis. The quantity levels of signature proteins investigated through LCSM/IEM demonstrated variability among different types, with AL-κ amyloidosis appeared to have a lower level. Not applicable.

Early prediction of acute kidney injury (AKI) may provide a crucial opportunity for AKI prevention. To date, no prediction model targeting AKI among general hospitalized patients in developing countries has been published. Here we show a simple, real-time, interpretable AKI prediction model for general hospitalized patients developed from a large tertiary hospital in China, which has been validated across five independent, geographically distinct, different tiered hospitals. The model containing 20 readily available variables demonstrates consistent, high levels of predictive discrimination in validation cohort, with AUCs for serum creatinine-based AKI and severe AKI within 48 h ranging from 0.74–0.85 and 0.83–0.90 for transported models and from 0.81–0.90 and 0.88–0.95 for refitted models, respectively. With optimal probability cutoffs, the refitted model could predict AKI at a median of 72 (24–198) hours in advance in internal validation, and 54–90 h in advance in external validation. Broad application of the model in the future may provide an effective, convenient and cost-effective approach for AKI prevention. Early prediction of Acute kidney injury (AKI) may be crucial for AKI prevention. Here the authors present a simple, real-time, interpretable, AKI prediction model for hospitalized patients, based on routinely collected electronic health records data.

Patients with light chain proximal tubulopathy (LCPT) typically overproduce abnormal immunoglobulin-free light chains (FLCs). They easily pass through the glomerulus into the proximal tubules. When the endosomal system fails to catabolize abnormal FLCs, it results in their accumulation in cytoplasm of proximal tubule cells (PTCs), forming inclusions or numerous lysosomes. Particular types of abnormal FLCs have been implicated in the onset of tubulopathies, suggesting that the amino acid (AA) sequence of FLCs may play a crucial role in the pathogenesis. This study aimed to determine the AA sequences of patient-derived FLCs and try to explain its relationship with intracellular crystal formation. The complete amino acid sequences of FLCs from five patients with LCPT were detected using an innovative de novo protein sequencing workflow. One patient (κPWL) did not exhibit crystalline histopathological lesions, whereas the other four patients showed crystalline lesions (κDEH, κWJJ, κWWJ, and κZGN). In this study, the degradation of FLCs in LCPT by human CtsB, CtsD and CtsL was tested under ideal in vitro conditions. An AI model AlphaFold3 was used to compare the structural variations of different FLCs, providing insights into the underlying crystallization mechanism. All pathogenic FLCs were highly homologous to the same germline counterpart, IGKV1-33. Kinetic studies of FLC digestion by the lysosomal enzyme CtsD revealed the production of a protease-resistant ∼12 kDa fragment in FLCs associated with crystalline LCPT. The CtsD-digested fragments of κ FLCs causing tubular crystallization corresponded to the VJ regions, whereas the λ FLC leading to tubular crystallization was linked to the C region. Site-directed mutagenesis in the variable domain may suppress the formation of intracellular crystals, which likely resulted from a change in hydrogen bonds leading to an alteration in folding. The generation of a proteolysis-resistant fragment from FLCs in crystalline LCPT by CtsD may be a common feature of this class of FLCs. Key amino acids may determine intracellular crystallization.