Renal involvement of IgG4-related disease (IgG4-RD), collectively termed IgG4-related kidney disease (IgG4-RKD), most commonly manifests as tubulointerstitial nephritis (TIN) but can also manifest as membranous glomerulonephritis (MGN) and acute interstitial nephritis (AIN) as a histologic subtype of IgG4-related TIN (IgG4-TIN). IgG4-related retroperitoneal fibrosis (IgG4-RPF) can cause obstructive kidney disease with or without active parenchymal IgG4-RKD. IgG4-RD is a clinicopathological diagnosis, requiring correlation of clinical, laboratory, radiological, and histological findings to identify features of IgG4-RD and rule out mimickers. Histopathologic features of IgG4-RD in tissue include a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, typically accompanied by so-called "storiform" fibrosis. Important mimics of IgG4-RKD include infection, malignancy, antineutrophil cytoplasmic autoantibody (ANCA)-associated disease, idiopathic multicentric Castleman disease, Rosai-Dorfman-Destombes disease and Sjögren Disease (SjD). Mimickers of IgG4-RPF include lymphoma, Erdheim-Chester disease, and idiopathic RPF. IgG4-RKD and IgG4-RPF are responsive to the systemic therapies used for IgG4-RD in general. Corticosteroids are the traditional first line therapy; however, B cell-targeted therapies, including rituximab, inebilizumab, and obexelimab are more potent and less toxic than steroids. Further trials are currently being conducted on newer medications that target signaling pathways and immune cells involved in the pathogenesis of IgG4-RD. Early recognition and treatment are critical to prevent irreversible organ damage. This review summarizes the current understanding of the pathogenesis, clinical spectrum, diagnostic approach, and management strategies for IgG4-RD, IgG4-RKD, and IgG4-RPF.

Tubulointerstitial diseases represent a heterogeneous group of kidney diseases with diverse causes and overlapping histopathologic and immunophenotypic patterns. Unlike glomerular disease, tubulointerstitial diseases have lacked specificity and standardized classification, but greater diagnostic precision is now possible and is necessary as nephrology enters an era of personalized medicine. This review provides an updated etiologic and attributive framework for tubulointerstitial nephritis/nephropathy (TIN) and tubular injury with 8 categories: drug effect, autoimmune/immune-mediated, infection-associated, hereditary/genetic, toxic/metabolic, monoclonal protein-associated, mimics of TIN, and idiopathic/other, recognizing overlap between these forms. This review highlights recently described or elucidated tubulointerstitial diseases such as immune checkpoint inhibitor-associated TIN, IgG4-related TIN, IgM plasma cell TIN, and VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. The milestones of IgG4-related TIN exemplify how a TIN disease entity evolves and can serve as a model for the recognition of new TIN entities. Looking forward, new biopsy-based technologies, digital pathology, and artificial intelligence can refine classification, enable precision diagnostics, and help to discover new entities. Continued collaborative efforts will be required to translate these advances into clinical practice and improved outcomes.

The XVIIth Banff meeting for transplant pathology was held in Paris, France, from September 16, 2024 to September 20, 2024, hosted by the Paris Institute for Transplantation & Organ Regeneration. The Banff 2024 meeting resulted in no changes to the Banff kidney classification. Important outputs of the meeting were a reaffirmation of the clinical usefulness of the clinical reasoning framework and flowchart for cases with microvascular inflammation/antibody-mediated rejection introduced at the Banff 2022 meeting and the introduction of a similar flowchart for tubulointerstitial inflammation and intimal arteritis (v lesion). The meeting highlighted the complexity of the immunologic processes (alloimmune and others) that lead to allograft inflammation and the need to strengthen the Banff system for differential diagnostic reasoning. Guidance is put in place for cases with incomplete/mixed phenotypes, which acknowledges the limits of our understanding. A proposal for potential future implementation of activity and chronicity indices was discussed, as well as digital and biopsy-based molecular tools that have the potential to help transform the classification into a probabilistic tool reflective of the underlying immunologic processes. Finally, guidelines for reporting of glomerular disease in the posttransplant setting were developed.

ObjectiveTo quantitatively examine immune cell markers and spatial distribution in human diabetic kidney disease (DKD) to enhance understanding of the inflammatory landscape contributing to injury. Maladaptive inflammation is an underrecognized contributor to DKD pathogenesis and progression and remains undertreated.Patients and methodsNanoString GeoMx™ Digital Spatial Profiling technology targeted antibodies labeled with unique oligonucleotide barcode in kidney biopsy [DKD (n=5), tubulointerstitial nephritis (TIN; n=4), and normal (n=2)] with regions of interest selection of compartments (glomeruli, tubules, interstitium). Inflammation-related proteins were analyzed with differential expression through linear mixed modeling.ResultsCompared to normal tissue, inflammatory cell surface protein markers were increased in DKD tubules and interstitium. Markers of T cells (CD4, CD44), macrophages (CD68; proinflammatory), and antigen-presenting cells (APCs; CD40 and CD11c) were increased across all DKD compartments (vs. normal). Macrophage (CD163; prorepair) marker was increased in DKD tubules and interstitium (vs. normal). Fewer differences were observed in glomeruli for normal vs. DKD or TIN vs. DKD groups. CD66b+ (granulocytes) cell marker was higher in DKD (vs. TIN). As expected, TIN had higher levels of T cell and macrophage markers in tubules and interstitium (vs. DKD). Interestingly, CD34, a hematopoietic stem cell and endothelial cell marker, was lower in DKD tubules and interstitium (vs. normal) but higher in DKD (vs. TIN).ConclusionNanoString GeoMx DSP technology may fulfil a role in enhancing the understanding the inflammatory landscape engaged in DKD pathogenesis as well as measuring response to therapy. Moreover, additional investigations of CD34 progenitor cell depletion in DKD may be warranted.

Introduction: The incidence of recurrent lupus nephritis (RLN) after kidney transplantation (KTx) varies with higher rates of RLN reported in surveillance biopsy-based studies (vs. clinically indicated biopsies). Methods: We present a multisite retrospective study evaluating surveillance and clinically indicated biopsies in 209 first KTx recipients who had native lupus disease. Results: Of the 112 patients with satisfactory material for comprehensive histology, RLN was observed in 40 (35.7%). We describe the pathology of histologic RLN (HRLN; 40%) and clinical RLN (CRLN; 60%). African Americans had the highest recurrence rate (48.3%) of whom 50% had CRLN. HRLN was noted as early as 18 days, with early diagnosis (< 3 months of follow-up time) using surveillance biopsies. Mesangioproliferative pattern of glomerular injury (˷ class II lupus nephritis [LN] by International Society of Nephrology/Renal Pathology Society) was the most frequent pattern of RLN. IgG dominance or codominance was the most frequent Ig staining pattern. A full-house pattern of staining was only seen in 6% of HRLN and 37% of CRLN. C4d stain, as a stand-alone immunofluorescence (IF) test, was performed in the index renal allograft biopsy in 37.5% of patients, with RLN, prompting evaluation with a full IF panel. Electron microscopy (EM) confirmed the findings on IF. Graft loss because of lupus-associated pathology was observed in 50% of RLN subjects, of which thrombotic microangiopathy was seen in 25%. Conclusion: Our study demonstrates that RLN is frequent and may be clinically quiescent. Sequential biopsy evaluation provided an opportunity to study the natural evolution of the disease.

Naesens, Maarten MD, PhD; Cornell, Lynn D. MD; Seshan, Surya V. MD; Haas, Mark MD, PhD Author Information

OBJECTIVES:Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is an autoinflammatory disease caused by somatic mutation of UBA1 and affects multiple organ systems. Involvement of the kidneys is not well characterized. We aimed to investigate the incidence, risk factors and histopathologic features of acute kidney injury (AKI) in VEXAS syndrome. METHODS:Patients with genetically confirmed UBA1 mutation consistent with VEXAS were included. Charts were manually reviewed. Cox regression analysis was used to identify variables associated with time-to-first AKI event. For patients with a kidney biopsy, histopathologic findings were reviewed. RESULTS:Eighty-one patients were included, all white men, with a mean age of 66.3 ± 8.6 years. Median (IQR) follow up was 3.5 (2.1-5.2) years during which 20 (25%) developed AKI and 22% died. AKI relapsed in 90% of cases for a median of 6 times during the follow up period. Cumulative incidence estimates (95% CI) for AKI at 1, 3 and 5 years were 6.2% (0.80-11.3%), 16.7% (7.5-25.0%) and 27.9% (14.9-38.9%), respectively. Age and baseline C-reactive protein (CRP) were significantly associated with time-to-first AKI event. Six patients underwent a kidney biopsy. Findings included, plasma cell-rich interstitial nephritis (n = 3), neutrophilic-rich interstitial inflammation (n = 1), leukocytoclastic peritubular capillaritis (n = 1) and acute tubular injury (n = 1). AKI responded well to treatment with glucocorticoids but had relapse upon tapering. CONCLUSION:AKI is an underrecognized feature of VEXAS occurring in 25% of patients in this cohort. Age at diagnosis and CRP were associated with time to first AKI event during follow up. Plasma cell-rich interstitial nephritis was the most common histopathologic finding.

INTRODUCTION:The diagnosis of antibody-mediated rejection (AMR) requires input from several transplant professionals. Bringing clinical and laboratory experts together may help standardize care. Yet, little is known about current global practices of multidisciplinary meetings for AMR management. METHODS:The Banff Antibody-Mediated Injury Working Group approached professional societies worldwide to distribute a survey on the availability, content, participants, perceived value, and barriers to the implementation of multidisciplinary meetings. RESULTS:Four hundred two transplant professionals from six continents caring for kidney (90.55%), liver (21.14%), pancreas (20.65%), heart (15.17%), and lung (14.18%) transplant recipients participated in the survey, and 302 (75.12%) reported attending multidisciplinary meetings. Multidisciplinary meetings were more prevalent in academic centers, in high- versus low-to-middle-income regions (81.03% and 65.99%, respectively; p < 0.001), and in mid-to-large size transplant programs compared to smaller programs. Perceived value included continued professional development (97.68%) and trainee education (95.70%). AMR was reported to be discussed at these meetings by 217 respondents with case presentations reviewing patient characteristics, histology, and HLA antibody data. A third of the respondents reviewed non-HLA/pathogenic autoantibodies and/or molecular diagnostics, with the latter being more frequently applied in high- versus low-to-middle-income regions (46.71% and 12.31%, respectively; p < 0.001). AMR case presentations allowed diagnosis revision, actionable management plans and were perceived as improving care. The primary barrier to the implementation of multidisciplinary meetings (63.27%) was the unavailability of transplant professionals (e.g., transplant immunologists). CONCLUSION:Facilitating multidisciplinary meetings through the remote participation of pertinent experts and incentivizing participation through remuneration, protected time, or continued medical education may help standardize AMR diagnosis and harmonize its management.

The Banff classification for kidney transplant pathology dichotomizes the rejection continuum into distinct diagnostic categories, introducing artificial cutoff points and threshold effects. To better reflect the underlying disease spectrum, in this cohort study of 19,500 biopsies from 8873 patients across 10 centers worldwide, we developed two indices for quantifying antibody-mediated rejection/microvascular inflammation and T-cell-mediated rejection/tubulointerstitial inflammation from histological lesion scores and calculated indices for overall activity and chronicity. These indices demonstrate excellent discrimination for the main diagnostic categories of rejection (AUCs from 0.95 to 0.99), with consistent performance across derivation and validation datasets. These indices strictly confine intermediate phenotypes to low index values and are associated to graft failure even within the diagnostic categories, thus reflecting the underlying rejection continuum. In this work, we demonstrate that four continuous indices provide implementable and interpretable global evaluation of kidney transplant histology that align with the continuous nature of the rejection process regardless of the underlying disease cause.

The spectrum of kidney lesions associated with monoclonal gammopathy has significantly expanded over the past 2 decades, with description of new entities and variants of old entities. Pathologic diagnosis is challenging because of lesional complexity, heterogeneity, and reliance on electron microscopy and ancillary techniques. A lack of precise pathologic definitions and uniform terminology has hampered diagnostic accuracy. To address these challenges, the Renal Pathology Society and International Kidney and Monoclonal Gammopathy Research Group jointly tasked a working group of nephropathologists and nephrologists to establish consensus-based terminology and definitions for monoclonal gammopathy-associated kidney lesions. Participants included experts in the field with international representation. This report presents their recommendations. For each lesion, prerequisite (mandatory) diagnostic criteria and supportive (nonmandatory) features are proposed. New terminology is provided for some lesions. Application of standardized terminology and definitions should help harmonize kidney biopsy diagnosis with precision therapy in the monoclonal gammopathy-associated kidney disorders.

INTRODUCTION:Most newly discovered membranous nephropathy (MN) antigens have been mutually exclusive, but there are rare cases of dual antigen MN based on immunohistochemistry (IHC)/immunofluorescence (IF) or serologic testing. Here, we searched for cases of dual antigen MN at Mayo Clinic and Arkana Laboratories with the diagnosis established by light/electron microscopy and IF. METHODS:At Mayo Clinic, we performed laser capture microdissection of glomeruli followed by liquid chromatography tandem mass spectrometry (LC MS/MS) on paraffin-embedded kidney biopsy tissue to detect 12 MN antigens. RESULTS:Nine cases of dual antigen MN (four at Mayo Clinic, five at Arkana Laboratories) were confirmed by both LC MS/MS and IHC/IF. The detected antigens were NELL1 + CNTN1 (two cases), NCAM1 + EXT1/2 (two cases), and one case each NDNF + NELL1, NELL1 + PLA2R1, THSD7A + PLA2R1, PCDH7 + PLA2R1, and CNTN1 + PCDH7. Median age at diagnosis was 68 years (range 23-84). Eight patients presented with nephrotic syndrome and microscopic hematuria. Median serum creatinine at diagnosis was 1 mg/dL. The underlying conditions, when present, and serological characteristics, correlated with the involved antigens. The frequency at Mayo Clinic was 2.6% of PLA2R1-negative MN cases. CONCLUSIONS:Given that IHC/IF and LC MS/MS for MN antigen detection are typically not pursued in PLA2R1-associated MN, dual-antigen MN is likely underdiagnosed. Dual-antigen MN can involve a variety of MN antigens, including those that are podocyte-expressed, transmembrane, or secreted. Most patients with MN present with nephrotic syndrome and microscopic hematuria. Further studies are needed to understand the pathophysiology of dual-antigen MN and determine their role both in the therapeutic approach and clinical outcomes. Our findings suggest that LC MS/MS is a valuable methodology for detection of dual antigen MN.

Introduction:IgG4-related disease (IgG4-RD) is a systemic immune-mediated disease that can involve nearly any organ. IgG4-RD can affect the kidney in different disease patterns, collectively referred to as IgG4-related kidney disease (IgG4-RKD). Methods:We conducted a tissue-based cohort study with clinicopathological correlation in 125 patients with IgG4-RKD. Results:The mean age at biopsy (n = 120) or nephrectomy (n = 5) was 63 years; 80% were male. One hundred eighteen patients (94%) had IgG4-related tubulointerstitial nephritis (IgG4-TIN); 20 patients (16%) had IgG4-related membranous glomerulonephritis (IgG4-MGN; 13 with concurrent IgG4-TIN). The primary clinical indication for biopsy/nephrectomy was acute or chronic renal failure in 78%, proteinuria in 17%, and mass lesion(s) in 15% (with overlap in primary indication). Fifty-two percent patients (41/79) had abnormal radiographic findings, including masses in 30% (24/79). All patients with IgG4-MGN had proteinuria. Extrarenal involvement by IgG4-RD was present in 79%. Median serum creatinine at presentation was 2.5 mg/dl (range 0.7-12). Serum IgG and/or IgG4 was increased in 91% (53/58); hypocomplementemia was present in 56% (43/77). Light microscopy showed plasma cell-rich interstitial nephritis in all cases of IgG4-TIN. Ninety-two percent of patients showed increased IgG4+ plasma cells. Seven percent showed an acute interstitial nephritis (AIN) pattern, and 5% showed non-necrotizing arteritis. Tubular basement membrane immune deposits were present in 83% of IgG4-TIN. Treatment information was available for 71 patients; 62 were treated with immunosuppression. Of those with elevated creatinine, 72% (41/57) showed a treatment response. Conclusion:This largest tissue-based series more clearly defines the disease phenotype of IgG4-RKD.

In kidney transplantation, day-zero biopsies are used to assess organ quality and discriminate between donor-inherited lesions and those acquired post-transplantation. However, many centers do not perform such biopsies since they are invasive, costly and may delay the transplant procedure. We aim to generate a non-invasive virtual biopsy system using routinely collected donor parameters. Using 14,032 day-zero kidney biopsies from 17 international centers, we develop a virtual biopsy system. 11 basic donor parameters are used to predict four Banff kidney lesions: arteriosclerosis, arteriolar hyalinosis, interstitial fibrosis and tubular atrophy, and the percentage of renal sclerotic glomeruli. Six machine learning models are aggregated into an ensemble model. The virtual biopsy system shows good performance in the internal and external validation sets. We confirm the generalizability of the system in various scenarios. This system could assist physicians in assessing organ quality, optimizing allograft allocation together with discriminating between donor derived and acquired lesions post-transplantation.

In September 2022, in Banff, Alberta, Canada, the XVIth Banff meeting, corresponding to the 30th anniversary of the Banff classification, was held, leading to 2 recent publications. Discussions at the Banff meeting focused on proposing improvements to the Banff process as a whole. In line with this, a unique opportunity was offered to a selected group of 16 representatives from the pathology and transplant nephrology community, experts in the field of kidney transplantation, to review these 2 Banff manuscripts. The aim was to provide an insightful commentary, to gauge any prospective influence the proposed changes may have, and to identify any potential areas for future enhancement within the Banff classification. The group expressed its satisfaction with the incorporation of 2 new entities, namely “microvascular inflammation/injury donor-specific antibodies–negative and C4d negative” and “probable antibody-mediated rejection,” into category 2. These changes expand the classification, facilitating the capture of more biopsies and providing an opportunity to explore the clinical implications of these lesions further. However, we found that the Banff classification remains complex, potentially hindering its widespread utilization, even if a degree of complexity may be unavoidable given the intricate pathophysiology of kidney allograft pathology. Addressing the histomorphologic diagnosis of chronic active T cell–mediated rejection (CA TCMR), potentially reconsidering a diagnostic-agnostic approach, as for category 2, to inflammation in interstitial fibrosis and tubular atrophy and chronic active T cell–mediated rejection was also an important objective. Furthermore, we felt a need for more evidence before molecular diagnostics could be routinely integrated and emphasized the need for clinical and histologic context determination and the substantiation of its clinical impact through rigorous clinical trials. Finally, our discussions stressed the ongoing necessity for multidisciplinary decision-making regarding patient care.

A 31-year-old man had a history of sickle cell disease and developed advanced chronic kidney disease due to presumed sickle cell–associated nephropathy. He underwent pre-emptive deceased donor kidney transplantation. Within approximately 5 minutes after perfusion, the kidney was described grossly as dusky, but the renal artery and vein were patent by a Doppler ultrasound examination. A postperfusion time-zero biopsy was performed. The biopsy showed extensive occlusion of arterioles and glomerular and peritubular capillaries, with "thrombi" composed of red blood cells, along with fibrin and platelets, as seen by light microscopy (Figure 1).

Diseases are often first recognized in their most severe forms. After a disease is initially described and diagnostic criteria are proposed, we gain experience and may broaden the spectrum to include manifestations that may be related but do not have all of the characteristics of a disease as originally described. Typical anti–glomerular basement membrane (GBM) disease is a clinically severe disease, with severe acute kidney injury, often pulmonary hemorrhage, and a high rate of end-stage kidney disease (and death if untreated).

Background. Microvascular inflammation (MVI) is a key feature of antibody-mediated rejection (AMR) among patients with HLA donor-specific antibody (DSA), but MVI at AMR thresholds (Banff glomerulitis [g] + peritubular capillaritis [ptc] score >= 2) without DSA has been increasingly recognized. We aimed to determine the incidence of MVI among highly sensitized kidney transplant recipients without DSA. Methods. We performed a single-center, retrospective, matched cohort study comparing outcomes of kidney transplant recipients with cPRA >= 90% with preexisting DSA (n = 49), cPRA >= 90% without preexisting DSA (n = 47), and matched controls with cPRA = 0 without preexisting DSA (n = 49). Controls were matched by age, donor type, and transplant date. Indication and surveillance biopsies combined with annual de novo DSA screening were obtained. Results. Kidney transplant recipients with a cPRA >= 90% and no evidence of preexisting or de novo DSA had a higher incidence of MVI (glomerulitis + peritubular capillaritis >= 2) than patients with cPRA = 0 [35% (17/49) versus 12% (6/49), P = 0.0003] over a median (interquartile range) follow-up of 5 (4-6) y posttransplant. Among this cPRA >= 90% group without DSA, MVI persisted in 54% of cases on follow-up biopsy (7/13), and 24% (4/13) of cases developed transplant glomerulopathy (Banff cg score > 0). Conclusions. Highly sensitized transplant recipients have a high incidence of persistent and progressive MVI, even without DSA. The mechanisms underlying these histologic features needs to be elucidated, but this information is important to consider when making decisions about transplantation among highly sensitized individuals.