Recent years have seen an explosion of interest in the pathogenesis and therapy of immunoglobulin A nephropathy (IgAN). Large cohort studies have facilitated improvements in disease classification and prognosis, including the establishment and validation of a standard pathological classification, the Oxford classification. Landmark treatment studies published in the past several years have solidified a basic therapeutic approach, emphasizing the value of adding immunomodulatory drugs to supportive care for aggressive disease. There are currently a large number of therapies with diverse mechanisms of action in active development for IgAN, promising at least to enhance our understanding of key pathogenic pathways and, at best, to eventually prove useful in slowing or stopping the progression of IgAN. In this cutting-edge feature, we use a clinical case to review and discuss the current standard of care in the diagnosis and treatment of IgAN, as well as to highlight emerging approaches to treatment.

Introduction Collapsing glomerulopathy (CG) in the kidney allograft is an infrequent complication, encountered more often in recipients of kidneys from Black donors. Despite its poor prognosis, the genetic susceptibility of this complication remains incompletely understood. Methods We performed a retrospective study from two major North American transplant centers. We assessed 47 recipients of kidney allografts from Black donors that developed CG and were followed for a median of 2.9 years after transplantation. Donor apolipoprotein L1 (APOL1) genotypes were available in 44 patients with CG and compared with 560 recipients of kidneys from Black donors who did not develop CG. Results Transplant recipients with CG were 55% of Black race and 40% female, and CG developed at a median of 9.5 months post-transplantation. Donors harboring zero, one, and two APOL1 kidney-risk variants (KRVs) comprised 16%, 41%, and 43% of CG cases and 45%, 43%, and 12% of controls, respectively. Combining cases and controls, receipt of a kidney from donors with two KRVs was associated with a higher risk of CG compared with donors with zero KRVs (adjusted odds ratio=12.51 [95% confidence interval, 4.83 to 32.39], P < 0.001). Receipt of a kidney with one KRV was also associated with a higher risk of CG compared with donors with no KRVs, although with lower effect than those with two KRVs (adjusted odds ratio=3.39 [1.36 to 8.46], P = 0.009). Recipients of kidneys from donors with two KRVs, but not with one KRV, had lower graft survival when compared with donors with zero KRVs (adjusted hazard ratio=1.49 [1.03 to 2.16], P = 0.04). Conclusions Although the association of CG in the kidney allograft with donor APOL1 KRVs suggests possible dose-dependent effects, lower graft survival was only observed in recipients of kidneys with two KRVs. Identification of additional risk factors for CG may improve utilization of kidneys from Black donors, including these with APOL1 KRVs.

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: Hemophagocytic lymphohistiocytosis (HLH) is a clinicopathologic syndrome produced by dysregulated activation of the immune system. Acute kidney injury (AKI) and proteinuria have been infrequently described in the setting of HLH, and investigations of underlying histopathologic changes in the kidney are limited. Methods: To characterize kidney pathology in HLH, a retrospective review of 30 patients' clinical and laboratory data, and kidney tissue was performed (18 from autopsy, and 12 biopsied patients). Results: HLH was associated with infection (83%), autoimmune disease (37%), and malignancy (20%), including 30% with concurrent autoimmune disease and infection. Nephrological presentations included subnephrotic range proteinuria (63%), AKI (63%), hematuria (33%), chronic kidney disease (CKD, 20%), nephrotic range proteinuria (13%), and nephrotic syndrome (7%); and 40% of patients required hemodialysis (HD). Among the 12 patients who underwent kidney biopsy, 6 subsequently showed improved kidney function and the remainder had progressive CKD with most progressing to end -stage kidney disease. Autopsy patients had a median terminal admission of 1 month, and 33% of the biopsied patients died (ranging from 0.3-5 months post-biopsy). Variable pathologies were identified, including acute tubular injury (ATI, 43%), lupus nephritis (LN, 23%), collapsing glomerulopathy (17%), thrombotic microangiopathy (TMA, 17%), and cortical necrosis (10%). Most autopsied patients had significant kidney pathology other than ATI that likely contributed to kidney function decline. A majority of patients with HLH exhibited kidney dysfunction that likely contributed to the poor prognosis. Conclusion: Kidney dysfunction in HLH should not be assumed to be solely attributable to ATI, and in certain scenarios a kidney biopsy may be warranted.

RATIONALE & OBJECTIVE:Crystalglobulinemia is a rare syndrome characterized by intravascular crystallization of monoclonal immunoglobulins (MIg). Data on kidney involvement are limited to case reports. This series characterizes the clinicopathologic spectrum of crystalglobulin-induced nephropathy (CIN). STUDY DESIGN:Case series. SETTING & PARTICIPANTS:Nineteen CIN cases identified from the nephropathology archives of Mayo Clinic and Columbia University. CIN was defined by intravascular (extracellular) MIg crystals visible by light microscopy (LM) and electron microscopy (EM). RESULTS:Among the cases, 68% were male, and 65% were Caucasian (median age, 56 years). Most patients presented with severe acute kidney injury (AKI) (median creatinine, 3.5mg/dL), hematuria, and mild proteinuria (median, 1.1g/day). Common extrarenal manifestations were constitutional (67%), cutaneous (56%), and rheumatologic (50%). Fifty percent of cases had hypocomplementemia. The hematologic disorders were monoclonal gammopathy of renal significance (MGRS) (72%), lymphoma (17%), or myeloma (11%), with 65% of these disorders discovered concomitantly with CIN. All patients had MIg identified on serum protein electrophoresis/immunofixation (IgGκ in 65%). The serum free light chain ratio was outside the renal range in 40%, and bone marrow biopsy detected the responsible clone in 67%. On LM, crystals involved glomeruli (100%) and vessels (47%), often with an inflammatory reaction (89%) and fibrin (58%). All cases exhibited crystal substructures (mostly paracrystalline) by EM. Immunofluorescence on paraffin-embedded tissue was more sensitive than frozen tissue (92% vs 47%) for demonstrating the crystal composition (IgGκ in 63%). Follow-up observation (median, 20 months) was available in 16 patients. Eighty-one percent received steroids, 44% plasmapheresis, 38% hemodialysis, and 69% chemotherapy. Ninety-percent of patients who received clone-directed therapy achieved kidney recovery versus 20% of those who did not (P=0.02). LIMITATIONS:Retrospective design, small sample size. CONCLUSIONS:CIN is a rare cause of nephropathy associated with lymphoplasmacytic disorders (mostly MGRS) and typically presents with severe AKI and extrarenal manifestations. Diagnosis often requires immunofluorescence performed on paraffin-embedded kidney tissue. Prompt initiation of clone-directed therapy, coupled with corticosteroids and plasmapheresis, may lead to recovery of kidney function.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%e90% of cases of MN. Many of the forms of MN asso-ciated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen -based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

A 62-year-old man was referred for evaluation of chronic kidney disease. Medical history was notable for gastroesophageal reflux disease, hyperlipidemia, and λ monoclonal gammopathy of undetermined significance. Medications included omeprazole and simvastatin. Physical examination revealed blood pressure of 162/82 mm Hg and body mass index of 29 kg/m2 but was otherwise unremarkable. Serum creatinine level ranged from 1.36 to 1.49 mg/dl (estimated glomerular filtration rate, 50–55 ml/min per 1.73 m2) over 1 year. Urinalysis revealed 2+ protein, 1+ blood, and no glucose. The 24-hour urine protein level was 1.1 g/d.

Introduction: Immunofluorescence (IF) staining for IgG subclasses plays an important role in the classification of kidney disease. However, widely used IgG subclass-specific antibodies are now commercially unavailable. Thus, we compared alternative antibodies for performing IgG subclass staining.Methods: A total of 21 cases were stained by 3 different methods: direct IF using fluorescein isothiocyanate (FITC)-conjugated polyclonal antibodies against IgG1-4 (commercially unavailable method), direct IF using FITC-conjugated monoclonal antibodies (clones HP-6091, 6014, 6050, and 6025), indirect IF using monoclonal antibodies (clones HP-6069, 6002, 6050, and 6025), and FITC-conjugated polyclonal secondary antibody. For cases with discrepancy in IgG1 staining, additional direct IF using FITC-conjugated monoclonal antibody (clone 4E3) was performed.Results: Of 21 cases, 11 (52%) had no staining for IgG1 by direct IF using the clone HP-6091 despite >= 1+ staining by the direct IF using polyclonal antibodies. Similarly, direct IF for IgG1 using the clone 4E3 had negative result in all 10 cases with available tissue. However, indirect IF for IgG1 using the clone HP-6069 had similar staining intensity (within 1 order of magnitude) as direct IF using the polyclonal antibodies (10 of 10). Results of IF for IgG2, IgG3, and IgG4 were similar in most cases.Conclusion: The choice of antibodies influences the result of IgG subclass staining, especially for anti-IgG1 antibodies, in which 2 monoclonal antibodies (HP6091 and 4E3) appear less sensitive. Although this may be due to unaccounted variables and requires confirmation, our results may partially explain the difference in IgG1 staining in the literature and underscore the need for careful validation.

Introduction: Lysozyme-associated nephropathy (LyN), a rare cause of kidney injury in patients with chronic myelomonocytic leukemia (CMML), has not been well described to date. We report the clinico-pathologic spectrum of LyN from a multi-institutional series. Method: We identified 37 native kidney biopsies with LyN and retrospectively obtained clinicopathologic data.Results: Thirty-seven patients had a median age of 74 years and included 78% males. Their most common presentation was acute kidney injury (AKI) or AKI on chronic kidney disease (CKD) (66%) with median estimated glomerular filtration rate (eGFR) of 21.7 ml/min per 1.73 m2, and proteinuria of 1.7 g. A minority (15%) had partial Fanconi syndrome. Serum lysozyme levels were elevated in all tested. Hematologic disorder (n = 28, 76%) was the most common etiology, including CMML (n = 15), acute myeloid leukemia (n = 5), and myelodysplastic syndrome (MDS) (n = 5). Nonhematologic causes (n = 5, 14%), included metastatic neuroendocrine carcinoma (n = 3), sarcoidosis, and leprosy. Etiology was unknown in 4 (11%). Pathology showed proximal tubulopathy with abundant hypereosinophilic intracytoplasmic inclusions, with characteristic staining pattern by lysozyme immunostain. Mortality was high (8/30). However, among the 22 alive, including 85% treated, 7 had improved kidney function, including 1 who discontinued dialysis and 6 with increase in eGFR >15 ml/min per 1.73 m2 compared with eGFR at the time of biopsy.Conclusion: Increased awareness of the full clinicopathologic spectrum of LyN may lead to prompt diagnosis, earlier treatment, and potentially improved outcome of this rare entity. 2023 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY -NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Neural epidermal growth factor-like 1 protein (NELL-1) was first identified as a membranous antigen by Sethi et al.1 utilizing laser capture microdissection and mass spectrometry followed by immunostaining. NELL-1 is currently the most common non-phospholipaseA2 receptor (PLA2R) membranous antigen. Segmental membranous changes are well-described in NELL-1 membranous nephropathy (MN).2 NELL-1 MN has been linked to malignancy, use of traditional indigenous medicines, and lipoic acid (LA) supplementation, among other conditions.

A 45-year-old White woman with recently diagnosed type 2 diabetes mellitus and hypertension presented with acute kidney injury and septic shock with gram-positive bacteremia from a toe wound. She was treated with vancomycin and piperacillin-tazobactam followed by ertapenem. She had no exposure to medications before admission nor to osmotic agents. Physical examination showed a body mass index of 37 and no edema. Laboratory evaluation revealed serum creatinine 8.1 mg/dl, serum albumin 2.2 g/dl, serum glucose 487 mg/dl, and hemoglobin A1c 12.6%. Urinalysis demonstrated glucose 1000 mg/dl and ketone 80 mg/dl. Serologies were unremarkable.

Conventional immunofluorescence (IF) for kidney biopsies is generally performed on frozen sections and uses a panel of polyclonal antibodies directed against the constant regions of immunoglobulin heavy chains and light chains (LCs). Diagnosis of monoclonal gammopathy of renal significance (MGRS) currently relies on the detection of isotype and LC-restricted (monotypic) staining for heavy and LCs, supplemented by IgG subclass staining and paraffin IF in selected cases. Recently, Nasr et al.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar described the potential use of IF using polyclonal antibodies directed against the conformational epitope at the junction of the heavy and LC (HLC) constant regions (HLC-IF), including IgGκ, IgGλ, IgMκ, IgMλ, IgAκ, and IgAλ, for the evaluation of MGRS or other conditions with monotypic deposits.Using these new antibodies, Nasr et al.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar found that some cases with apparent monotypic glomerular deposits by conventional IF (i.e., cases that stain for only 1 heavy chain isotype and only 1 LC) may have polytypic staining by HLC-IF with reactivity for both κ- and λ-heavy chain pairs. Therefore, HLC-IF could be used to confirm or exclude monotypic composition of deposits in these cases, similar to IgG subclass staining.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Furthermore, they recommended that some cases that would be classified as MGRS based on conventional IF, such as proliferative glomerulonephritis (GN) with monoclonal immunoglobulin deposits (PGNMIDs), should not be categorized as MGRS if HLC-IF reveals staining for both IgGκ and IgGλ.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google ScholarGiven the potentially utility of HLC-IF in the diagnosis of MGRS (Figure 1), we sought to broaden the clinical experience with HLC-IF in an independent series of kidney biopsies, enriched with entities that had relatively small sample size in the study by Nasr et al.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Specifically, we evaluated 43 cases by direct HLC-IF for IgGκ and IgGλ and 22 cases by direct HLC-IF for IgAκ and IgAλ (including 12 controls; see Supplementary Methods).Results are summarized in Table 1. There were 20 biopsies with PGNMID which exhibited, by definition, monotypic deposits by conventional IF, including 12 with IgG3κ, 5 IgG1κ, 1 IgG1λ, 1 IgG2κ, and 1 IgG3λ. The cohort was unintentionally enriched with patients with malignancy or paraproteinemia including 1 patient with multiple myeloma and PGNMID-IgG3κ, 3 patients with B-cell lymphoma (not further classified) including 2 with PGNMID-IgG3κ and 1 with PGNMID-IgG2κ, and 5 additional patients with a documented paraprotein (all PGNMID-IgG3κ). HLC-IF results revealed both IgGκ and IgGλ in only 2 of 20 patients with PGNMID (10%), both of whom had IgG1κ deposits by conventional IF. Of the 2 patients, 1 was 23 years old without detectable paraprotein or hematolymphoid malignancy and the other was 69 years old with free κ LCs on urine immunofixation but no hematolymphoid neoplasm.Table 1HLC-IF on independent samples of glomerular diseases with monotypic or bitypic deposits; comparison of results at Columbia University and Mayo ClinicPathologyCUIMCMayoMonotypic deposits by conventional IFNumber of cases polytypic by HLC-IFMonotypic deposits by conventional IFNumber of cases polytypic by HLC-IFPGNMIDIgG1κ2/5IgG1λ0/1IgG2κ0/1IgG3κ0/12IgG3κ2/7IgG3λ0/1IgG3λ0/3Total2/20Total2/10Immunotactoid GNIgG1κ2/2IgG1λ0/3IgG1κ and IgG2κ1/1IgG2κ2/2Total5/8Not evaluatedMonotypic or bitypic MNIgG1κ1/3IgG3λ0/1IgG1κ and IgG3κ2/2IgG3κ0/1Total3/6Total0/1Monotypic fibrillary GNIgG1κ2/3IgGλ3/6Total2/3Total3/6Monotypic or bitypic anti-GBM diseaseIgG1κ2/2IgGκ0/1IgG1λ0/3IgGλ0/2IgG1λ and IgG4λ1/1IgMκ0/1IgAλ1/2Total3/6Total1/6LC-restricted IgA nephropathy/vasculitisaThese cases were stained with IgAκ and IgAλ HLC-IF.IgAκ0/8IgAλ3/14IgAλ6/12Total3/22Total6/12CUIMC, Columbia University Irving Medical Center; GBM, glomerular basement membrane; GN, glomerulonephritis; HLC, heavy and light chain; IF, immunofluorescence; LC, light chain; MN, membranous nephropathy; PGNMID, proliferative glomerulonephritis with monoclonal immunoglobulin deposits.a These cases were stained with IgAκ and IgAλ HLC-IF. Open table in a new tab HLC-IF was performed on 7 biopsies with immunotactoid GN (ITG) with monotypic deposits based on conventional IF with IgG subclass staining, including 3 with IgG1λ, 2 IgG1κ, and 2 IgG2κ, and 1 with bitypic staining for IgG1κ and IgG2κ. Among the 7 with monotypic ITG by conventional IF, 4 had chronic lymphocytic leukemia (including 2 patients with IgG1κ, 1 with IgG1λ, and 1 with IgG2κ deposits) and 2 had monoclonal gammopathy in the absence of chronic lymphocytic leukemia (1 with IgG1λ deposits and 1 with IgG2κ deposits). The remaining patient with monotypic ITG, and the patient with bitypic ITG, had no detectable paraprotein or hematolymphoid malignancy. HLC-IF results revealed both IgGκ and IgGλ in 4 of the 7 with monotypic ITG (57%), including 2 with IgG1κ and 2 with IgG2κ, and in the single patient with bitypic ITG. Not surprisingly, in 4 of the 5 cases with polytypic staining by HLC-IF, there was greater intensity of staining for the IgG-LC pair that had been originally identified in the monotypic deposits by conventional IF. Of note, in 3 of the 4 patients with chronic lymphocytic leukemia, the deposits were polytypic with HLC-IF.There were 6 patients who had LC-restricted membranous nephropathy,2Best Rocha A. Larsen C.P. Membranous glomerulopathy with light chain-restricted deposits: a clinicopathological analysis of 28 cases.Kidney Int Rep. 2017; 2: 1141-1148https://doi.org/10.1016/j.ekir.2017.07.008Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar including 3 with IgG1κ monotypic deposits, 1 with IgG3λ monotypic deposits, and 2 with bitypic IgG1κ and IgG3κ deposits. One patient with monotypic deposits (IgG1κ) had chronic lymphocytic leukemia and 1 patient with bitypic deposits had lymphoma of mucosa-associated lymphoid tissue (with IgM paraprotein). The remaining 4 patients did not have paraproteinemia or hematolymphoid malignancy. HLC-IF results revealed staining for both IgGκ and IgGλ in 1 patient with monotypic IgG1κ deposits and in both patients with bitypic deposits by conventional IF.Six patients had LC-restricted atypical antiglomerular basement membrane disease,3Nasr S.H. Collins A.B. Alexander M.P. et al.The clinicopathologic characteristics and outcome of atypical anti-glomerular basement membrane nephritis.Kidney Int. 2016; 89: 897-908https://doi.org/10.1016/j.kint.2016.02.001Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar including 2 with IgG1κ-restriction, 3 with IgG1λ-restriction, and 1 with bitypic IgG1λ and IgG4λ. One patient with IgG1κ deposits had a serum IgGκ and free κ paraprotein, the remaining 5 had no evidence of paraproteinemia, and none had evidence of hematolymphoid malignancy. HLC-IF results revealed both IgGκ and IgGλ in both cases with IgG1κ restriction and in the case of bitypic IgG1λ and IgG4λ.HLC-IF was performed on 3 biopsies with monotypic DNAJB9-associated fibrillary GN and IgG1κ-restricted deposits.4Kudose S. Canetta P. Andeen N.K. et al.Diagnostic approach to glomerulonephritis with fibrillar IgG deposits and light chain restriction.Kidney Int Rep. 2021; 6: 936-945https://doi.org/10.1016/j.ekir.2021.01.001Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,5Said S.M. Leung N. Alexander M.P. et al.DNAJB9-positive monotypic fibrillary glomerulonephritis is not associated with monoclonal gammopathy in the vast majority of patients.Kidney Int. 2020; 98: 498-504https://doi.org/10.1016/j.kint.2020.02.025Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar One patient had an IgGκ serum paraprotein, but none had evidence of hematolymphoid malignancy. HLC-IF results revealed both IgGκ and IgGλ in the 2 patients who lacked a detectable paraprotein and, oddly, were negative for both IgGκ and IgGλ in the other patient.We evaluated 22 biopsies with LC restricted, IgA-dominant staining including 16 cases of apparent IgA nephropathy and 6 with IgA vasculitis. Among the 22 patients, only 1 had a serum M-spike (IgGκ and free κ) and none had a history of malignancy. HLC-IF result was positive solely for IgAκ in all 8 cases with IgAκ restriction by conventional IF. In contrast, HLC-IF results revealed both IgAκ and IgAλ in 3 of 14 biopsies (21%) with IgAλ restriction by conventional IF. Notably HLC-IF results in 12 control cases revealed findings concordant with conventional IF.Our results extend and refine the findings by Nasr et al.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar In our cohort, HLC-IF detected polytypic glomerular deposits in approximately 30% of cases that display monotypic deposits by conventional IF. HLC-IF seems most useful in monotypic or bitypic forms of membranous nephropathy, fibrillary GN, atypical antiglomerular basement membrane disease, and in a few cases of λ-restricted IgA nephropathy, because almost all with polytypic HLC-IF results had no evidence of hematolymphoid malignancy or paraproteinemia that matched the glomerular deposits. This was particularly notable for monotypic DNAJB9-associated fibrillary GN, as recent reports suggest that this entity should not be considered a form of MGRS.4Kudose S. Canetta P. Andeen N.K. et al.Diagnostic approach to glomerulonephritis with fibrillar IgG deposits and light chain restriction.Kidney Int Rep. 2021; 6: 936-945https://doi.org/10.1016/j.ekir.2021.01.001Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,5Said S.M. Leung N. Alexander M.P. et al.DNAJB9-positive monotypic fibrillary glomerulonephritis is not associated with monoclonal gammopathy in the vast majority of patients.Kidney Int. 2020; 98: 498-504https://doi.org/10.1016/j.kint.2020.02.025Abstract Full Text Full Text PDF PubMed Scopus (17) Google ScholarHLC-IF was of limited utility in excluding monotypic deposits in PGNMID, with detection of both IgGκ and IgGλ-heavy chain pairs in only 2 of 20 patients with PGNMID (10%), similar to the finding by Nasr et al.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar (2 of 10; 20%). This entity remains something of an enigma in that deposits reproducibly seem to have a monotypic composition despite the absence of a detectable paraprotein in 70% of patients. Similarly, HLC-IF was of limited utility in cases of κ-restricted IgA nephropathy/vasculitis.Importantly, our findings also suggest that the presence of both κ- and λ-heavy chain pairs by HLC-IF does not in and of itself exclude an association with paraproteinemia or hematolymphoid malignancy. Although coincidental associations cannot be excluded, this finding highlights the need for careful interpretation of HLC-IF results in the context of specific disease categories. In particular, among patients with monotypic ITG (most of whom have paraproteinemia or hematolymphoid malignancy), the combined results of conventional IF and HLC-IF suggest that, although monotypic deposits predominate in 2/3 cases, some of these cases have a smaller component of polytypic deposits that are best identified by HLC-IF.6Nasr S.H. Kudose S.S. Said S.M. et al.Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants.Kidney Int. 2021; 99: 410-420https://doi.org/10.1016/j.kint.2020.07.037Abstract Full Text Full Text PDF PubMed Scopus (15) Google ScholarLimitations of our data include the relatively small sample size, the limited availability of clinical data, and the inability to verify our data by an orthogonal non-antibody based method.In summary, we report an independent series of kidney biopsy specimens evaluated with HLC-IF. Our findings largely validate the findings by Nasr et al.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar and expand the literature on the utility of HLC-IF in the evaluation of selected kidney diseases. More experience is needed to define the role of HLC-IF in routine kidney biopsy practice.DisclosureAll the authors declared no competing interests. Conventional immunofluorescence (IF) for kidney biopsies is generally performed on frozen sections and uses a panel of polyclonal antibodies directed against the constant regions of immunoglobulin heavy chains and light chains (LCs). Diagnosis of monoclonal gammopathy of renal significance (MGRS) currently relies on the detection of isotype and LC-restricted (monotypic) staining for heavy and LCs, supplemented by IgG subclass staining and paraffin IF in selected cases. Recently, Nasr et al.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar described the potential use of IF using polyclonal antibodies directed against the conformational epitope at the junction of the heavy and LC (HLC) constant regions (HLC-IF), including IgGκ, IgGλ, IgMκ, IgMλ, IgAκ, and IgAλ, for the evaluation of MGRS or other conditions with monotypic deposits. Using these new antibodies, Nasr et al.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar found that some cases with apparent monotypic glomerular deposits by conventional IF (i.e., cases that stain for only 1 heavy chain isotype and only 1 LC) may have polytypic staining by HLC-IF with reactivity for both κ- and λ-heavy chain pairs. Therefore, HLC-IF could be used to confirm or exclude monotypic composition of deposits in these cases, similar to IgG subclass staining.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Furthermore, they recommended that some cases that would be classified as MGRS based on conventional IF, such as proliferative glomerulonephritis (GN) with monoclonal immunoglobulin deposits (PGNMIDs), should not be categorized as MGRS if HLC-IF reveals staining for both IgGκ and IgGλ.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Given the potentially utility of HLC-IF in the diagnosis of MGRS (Figure 1), we sought to broaden the clinical experience with HLC-IF in an independent series of kidney biopsies, enriched with entities that had relatively small sample size in the study by Nasr et al.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Specifically, we evaluated 43 cases by direct HLC-IF for IgGκ and IgGλ and 22 cases by direct HLC-IF for IgAκ and IgAλ (including 12 controls; see Supplementary Methods). Results are summarized in Table 1. There were 20 biopsies with PGNMID which exhibited, by definition, monotypic deposits by conventional IF, including 12 with IgG3κ, 5 IgG1κ, 1 IgG1λ, 1 IgG2κ, and 1 IgG3λ. The cohort was unintentionally enriched with patients with malignancy or paraproteinemia including 1 patient with multiple myeloma and PGNMID-IgG3κ, 3 patients with B-cell lymphoma (not further classified) including 2 with PGNMID-IgG3κ and 1 with PGNMID-IgG2κ, and 5 additional patients with a documented paraprotein (all PGNMID-IgG3κ). HLC-IF results revealed both IgGκ and IgGλ in only 2 of 20 patients with PGNMID (10%), both of whom had IgG1κ deposits by conventional IF. Of the 2 patients, 1 was 23 years old without detectable paraprotein or hematolymphoid malignancy and the other was 69 years old with free κ LCs on urine immunofixation but no hematolymphoid neoplasm. CUIMC, Columbia University Irving Medical Center; GBM, glomerular basement membrane; GN, glomerulonephritis; HLC, heavy and light chain; IF, immunofluorescence; LC, light chain; MN, membranous nephropathy; PGNMID, proliferative glomerulonephritis with monoclonal immunoglobulin deposits. HLC-IF was performed on 7 biopsies with immunotactoid GN (ITG) with monotypic deposits based on conventional IF with IgG subclass staining, including 3 with IgG1λ, 2 IgG1κ, and 2 IgG2κ, and 1 with bitypic staining for IgG1κ and IgG2κ. Among the 7 with monotypic ITG by conventional IF, 4 had chronic lymphocytic leukemia (including 2 patients with IgG1κ, 1 with IgG1λ, and 1 with IgG2κ deposits) and 2 had monoclonal gammopathy in the absence of chronic lymphocytic leukemia (1 with IgG1λ deposits and 1 with IgG2κ deposits). The remaining patient with monotypic ITG, and the patient with bitypic ITG, had no detectable paraprotein or hematolymphoid malignancy. HLC-IF results revealed both IgGκ and IgGλ in 4 of the 7 with monotypic ITG (57%), including 2 with IgG1κ and 2 with IgG2κ, and in the single patient with bitypic ITG. Not surprisingly, in 4 of the 5 cases with polytypic staining by HLC-IF, there was greater intensity of staining for the IgG-LC pair that had been originally identified in the monotypic deposits by conventional IF. Of note, in 3 of the 4 patients with chronic lymphocytic leukemia, the deposits were polytypic with HLC-IF. There were 6 patients who had LC-restricted membranous nephropathy,2Best Rocha A. Larsen C.P. Membranous glomerulopathy with light chain-restricted deposits: a clinicopathological analysis of 28 cases.Kidney Int Rep. 2017; 2: 1141-1148https://doi.org/10.1016/j.ekir.2017.07.008Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar including 3 with IgG1κ monotypic deposits, 1 with IgG3λ monotypic deposits, and 2 with bitypic IgG1κ and IgG3κ deposits. One patient with monotypic deposits (IgG1κ) had chronic lymphocytic leukemia and 1 patient with bitypic deposits had lymphoma of mucosa-associated lymphoid tissue (with IgM paraprotein). The remaining 4 patients did not have paraproteinemia or hematolymphoid malignancy. HLC-IF results revealed staining for both IgGκ and IgGλ in 1 patient with monotypic IgG1κ deposits and in both patients with bitypic deposits by conventional IF. Six patients had LC-restricted atypical antiglomerular basement membrane disease,3Nasr S.H. Collins A.B. Alexander M.P. et al.The clinicopathologic characteristics and outcome of atypical anti-glomerular basement membrane nephritis.Kidney Int. 2016; 89: 897-908https://doi.org/10.1016/j.kint.2016.02.001Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar including 2 with IgG1κ-restriction, 3 with IgG1λ-restriction, and 1 with bitypic IgG1λ and IgG4λ. One patient with IgG1κ deposits had a serum IgGκ and free κ paraprotein, the remaining 5 had no evidence of paraproteinemia, and none had evidence of hematolymphoid malignancy. HLC-IF results revealed both IgGκ and IgGλ in both cases with IgG1κ restriction and in the case of bitypic IgG1λ and IgG4λ. HLC-IF was performed on 3 biopsies with monotypic DNAJB9-associated fibrillary GN and IgG1κ-restricted deposits.4Kudose S. Canetta P. Andeen N.K. et al.Diagnostic approach to glomerulonephritis with fibrillar IgG deposits and light chain restriction.Kidney Int Rep. 2021; 6: 936-945https://doi.org/10.1016/j.ekir.2021.01.001Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,5Said S.M. Leung N. Alexander M.P. et al.DNAJB9-positive monotypic fibrillary glomerulonephritis is not associated with monoclonal gammopathy in the vast majority of patients.Kidney Int. 2020; 98: 498-504https://doi.org/10.1016/j.kint.2020.02.025Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar One patient had an IgGκ serum paraprotein, but none had evidence of hematolymphoid malignancy. HLC-IF results revealed both IgGκ and IgGλ in the 2 patients who lacked a detectable paraprotein and, oddly, were negative for both IgGκ and IgGλ in the other patient. We evaluated 22 biopsies with LC restricted, IgA-dominant staining including 16 cases of apparent IgA nephropathy and 6 with IgA vasculitis. Among the 22 patients, only 1 had a serum M-spike (IgGκ and free κ) and none had a history of malignancy. HLC-IF result was positive solely for IgAκ in all 8 cases with IgAκ restriction by conventional IF. In contrast, HLC-IF results revealed both IgAκ and IgAλ in 3 of 14 biopsies (21%) with IgAλ restriction by conventional IF. Notably HLC-IF results in 12 control cases revealed findings concordant with conventional IF. Our results extend and refine the findings by Nasr et al.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar In our cohort, HLC-IF detected polytypic glomerular deposits in approximately 30% of cases that display monotypic deposits by conventional IF. HLC-IF seems most useful in monotypic or bitypic forms of membranous nephropathy, fibrillary GN, atypical antiglomerular basement membrane disease, and in a few cases of λ-restricted IgA nephropathy, because almost all with polytypic HLC-IF results had no evidence of hematolymphoid malignancy or paraproteinemia that matched the glomerular deposits. This was particularly notable for monotypic DNAJB9-associated fibrillary GN, as recent reports suggest that this entity should not be considered a form of MGRS.4Kudose S. Canetta P. Andeen N.K. et al.Diagnostic approach to glomerulonephritis with fibrillar IgG deposits and light chain restriction.Kidney Int Rep. 2021; 6: 936-945https://doi.org/10.1016/j.ekir.2021.01.001Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,5Said S.M. Leung N. Alexander M.P. et al.DNAJB9-positive monotypic fibrillary glomerulonephritis is not associated with monoclonal gammopathy in the vast majority of patients.Kidney Int. 2020; 98: 498-504https://doi.org/10.1016/j.kint.2020.02.025Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar HLC-IF was of limited utility in excluding monotypic deposits in PGNMID, with detection of both IgGκ and IgGλ-heavy chain pairs in only 2 of 20 patients with PGNMID (10%), similar to the finding by Nasr et al.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar (2 of 10; 20%). This entity remains something of an enigma in that deposits reproducibly seem to have a monotypic composition despite the absence of a detectable paraprotein in 70% of patients. Similarly, HLC-IF was of limited utility in cases of κ-restricted IgA nephropathy/vasculitis. Importantly, our findings also suggest that the presence of both κ- and λ-heavy chain pairs by HLC-IF does not in and of itself exclude an association with paraproteinemia or hematolymphoid malignancy. Although coincidental associations cannot be excluded, this finding highlights the need for careful interpretation of HLC-IF results in the context of specific disease categories. In particular, among patients with monotypic ITG (most of whom have paraproteinemia or hematolymphoid malignancy), the combined results of conventional IF and HLC-IF suggest that, although monotypic deposits predominate in 2/3 cases, some of these cases have a smaller component of polytypic deposits that are best identified by HLC-IF.6Nasr S.H. Kudose S.S. Said S.M. et al.Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants.Kidney Int. 2021; 99: 410-420https://doi.org/10.1016/j.kint.2020.07.037Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Limitations of our data include the relatively small sample size, the limited availability of clinical data, and the inability to verify our data by an orthogonal non-antibody based method. In summary, we report an independent series of kidney biopsy specimens evaluated with HLC-IF. Our findings largely validate the findings by Nasr et al.1Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170https://doi.org/10.1016/j.kint.2021.02.038Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar and expand the literature on the utility of HLC-IF in the evaluation of selected kidney diseases. More experience is needed to define the role of HLC-IF in routine kidney biopsy practice. DisclosureAll the authors declared no competing interests. All the authors declared no competing interests. The authors thank Yuancheng Wang at the Columbia Renal Pathology Laboratory for technical assistance with HLC-IF. The authors thank the Binding Site (Birmingham, United Kingdom) for gifting the HLC-IF reagents used in this study. Supplemental Material Download .pdf (.6 MB) Help with pdf files Supplementary File (PDF)Supplementary Methods (PDF). Download .pdf (.6 MB) Help with pdf files Supplementary File (PDF) Supplementary Methods (PDF).

Light-chain (AL) amyloidosis is a severe complication of plasma-cell disorders or B-cell lymphoma, secondary to monoclonal Ig light chain (LC) deposition in tissues and organs. Kidney involvement is found in two-thirds of patients at diagnosis.1 AL amyloidosis frequently affects glomeruli and vessels, and the interstitium in roughly half of the cases.2 Originally, the term "amyloidosis" was used exclusively to describe extracellular deposits that generate birefringence under polarized light after Congo red staining.

Membranous nephropathy (MN) is etiologically associated with circulating autoantibodies against M-type phospholipase A2 receptor (PLA2R) in approximately 80% of cases (when secondary etiologies are excluded).1 Whereas a kidney biopsy may be unnecessary to diagnose MN in patients with detectable serum anti-PLA2R antibody and preserved estimated glomerular filtration rate, a biopsy may reveal findings that alter therapy in patients with reduced estimated glomerular filtration rate.2,3 In this report, we describe a patient with PLA2R-associated MN who developed acute kidney injury with renal biopsy findings of concurrent anti-glomerular basement membrane (GBM) disease, and discuss diagnostic considerations for patients with MN and crescents.

Rare cases of immunoglobulin G (IgG)-dominant immune complex-mediated glomerulonephritis demonstrate immunoglobulin subclass restriction without light chain restriction. Some of these cases may represent proliferative glomerulonephritis with monotypic immunoglobulin deposits (PGNMID) in which monotypic immunoglobulin is obscured by coexisting polytypic immunoglobulin. However, rigorous demonstration of this possibility is lacking to date. Here, we describe a case of IgG3-restricted immune complex-mediated glomerulonephritis without light chain restriction that apparently "transformed" into IgG3κ-PGNMID in a subsequent biopsy. We demonstrate, using several ancillary techniques, including use of the newly described antibodies directed against the conformational epitope at the junctions of heavy and light chains (HLC-IF), that the first biopsy likely represents IgG3κ-PGNMID in which monotypic IgG3κ was hidden by polytypic IgM. This case underscores the need to consider PGNMID in a differential diagnosis of IgG-dominant immune complex-mediated glomerulonephritis without light chain restriction and highlights the potential utility of IgG subclass staining and HLC-IF in such cases to detect monotypic immunoglobulin that may be obscured by coexisting IgM and/or IgA deposits.

Allograft survival of deceased donor kidneys with suboptimal histology (DRTx/suboptimal histology: >10% glomerulosclerosis, >10% tubulointerstitial scarring, or >mild vascular sclerosis) is inferior to both DRTx with optimal histology (DRTx/optimal histology) and living donor kidneys irrespective of histologic changes (LRTx). In this report, we explored the reasons behind this guarded outcome with a special focus on the role of alloimmunity. We initially assessed gene expression in 39 time-zero allograft biopsies using the Nanostring 770 genes PanCancer Immune Profiling Panel. Subsequently, we studied 696 consecutive adult kidney allograft recipients that were grouped according to allograft type and histology at time-zero biopsy [DRTx/suboptimal histology (n = 194), DRTx/optimal histology (n = 166), and LRTx (n = 336)]. Part-1: Several immune pathways were upregulated in time-zero biopsies from DRTx/suboptimal histology (n = 11) compared to LRTx (n = 17) but not to DRTx/optimal histology (n = 11). Part-2: Amongst the three groups of recipients, DRTx/suboptimal histology had the highest incidence of acute rejection episodes, most of which occurred during the first year after transplantation (early rejection). This increase was mainly attributed to T cell mediated rejection, while the incidence of antibody-mediated rejection was similar amongst the three groups. Importantly, early acute T cell mediated rejection was a strong independent predictor for allograft failure in DRTx/suboptimal histology (adjusted HR: 2.13, P = 0.005) but not in DRTx/optimal histology nor in LRTx. Our data highlight an increased baseline immunogenicity in DRTx/suboptimal histology compared to LRTx but not to DRTx/optimal histology. However, our results suggest that donor chronic histologic changes in DRTx may help transfer such increased baseline immunogenicity into clinically relevant acute rejection episodes that have detrimental effects on allograft survival. These findings may provide a rationale for enhanced immunosuppression in recipients of DRTx with baseline chronic histologic changes to minimize subsequent acute rejection and to prolong allograft survival.