Characteristics and Outcomes of NELL1 Membranous Nephropathy in Lipoic Acid Users and Nonusers.

Introduction: Neural epidermal growth factor like 1 membranous nephropathy (NELL1 MN) is associated with various secondary etiologies. However, previous studies on the frequency of these associations and their impact on outcomes are limited. We report a large multiinstitutional series of patients with NELL1 MN with a focus on secondary associations, pathology findings, and their impact on outcome. Methods: We retrospectively reviewed clinicopathologic features of NELL1 MN from 3 institutions and analyzed clinical and histologic associations with outcome. Results: Of 70 patients, 53% were male with a median age of 66 years; median proteinuria was 5.9 g/d. NELL1 MN was associated with lipoic acid (36%), heavy nonsteroidal antiinflammatory drug (NSAID) use (27%), autoimmune disease (23%), malignancy (10% recent, 23% any), mercury exposure (1%), and 11% had no known secondary association. At median follow-up of 11 months, 72% achieved complete or partial remission. Remission rate was 91% in patients with lipoic acid-associated NELL1 MN and ≥6 months of follow-up. On multivariable analyses, patients with primary NELL1 MN (adjusted odds ratio [OR]: 19.7, P = 0.01) and increasing degree of tubular atrophy and interstitial fibrosis (IFTA) (adjusted OR 1.1, P = 0.01) were less likely to achieve any remission, whereas complete remission (CR) was associated with lipoic acid use (adjusted OR: 10.9, P = 0.04, 95% confidence interval [CI]: 1.2-100) and lesser degrees of IFTA (adjusted OR: 0.79, P = 0.16, 95% CI: 0.66-0.96). Conclusion: Our findings strengthen the association between lipoic acid and NELL1 MN. Furthermore, our findings suggest that discontinuation of lipoic acid without immunosuppression should be considered as the first-line treatment.

Collapsing glomerulopathy is likely a major contributing factor for worse allograft survival in patients receiving kidney transplants from black donors.

Although a few registry-based studies have shown associations between receiving kidney allografts from Black donors and shorter allograft survival, detailed, large, single-center studies accounting for common confounding factors are lacking. Furthermore, pathologic alterations underlying this potential disparity have not been systematically studied. We performed a retrospective clinical-pathological study of kidney transplant recipients who received kidney allografts from either Black (n = 407) or White (n = 1,494) donors at Columbia University Irving Medical Center from 2005 to 2018, with median follow-up of 4.5 years post-transplantation. Black donor race was independently associated with allograft failure (adjusted HR = 1.34, p = 0.02) and recipients of kidney allografts from Black donors had a higher incidence of collapsing glomerulopathy [7.4% vs. 1.9%, OR = 4.17, p < 0.001]. When causes of allograft failure were examined, only allograft failure following development of collapsing glomerulopathy was more frequent in recipients of allografts from Black donors [15% vs. 5%, OR = 3.16, p = 0.004]. Notably, when patients who developed collapsing glomerulopathy were excluded from analysis, receiving kidney allografts from Black donors was not independently associated with allograft failure (adjusted HR = 1.24, p = 0.10). These findings revealed that, compared with recipients of kidney allografts from White donors, recipients of kidneys from Black donors have modestly shorter allograft survival and a higher probability of developing collapsing glomerulopathy, which negatively impacts allograft outcome. Identification of collapsing glomerulopathy risk factors may help decrease this complication and improve allograft survival, which optimally may reduce racial disparities post-transplantation.

Kidney Dysfunction and Pathology in the Setting of Hemophagocytic Lymphohistiocytosis.

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.

Immunofluorescence Staining for IgG Subclass: Cause for Discrepancy in the Detection of IgG1.

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.

Clinicopathologic Spectrum of Lysozyme-Associated Nephropathy.

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 clinicopathologic 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.

Implementation and Feasibility of Clinical Genome Sequencing Embedded Into the Outpatient Nephrology Care for Patients With Proteinuric Kidney Disease.

Introduction: The diagnosis and management of proteinuric kidney diseases such as focal segmental glomerulosclerosis (FSGS) are challenging. Genetics holds the promise to improve clinical decision making for these diseases; however, it is often performed too late to enable timely clinical action and it is not implemented within routine outpatient nephrology visits. Methods: We sought to test the implementation and feasibility of clinical rapid genome sequencing (GS) in guiding decision making in patients with proteinuric kidney disease in real-time and embedded in the outpatient nephrology setting. Results: We enrolled 10 children or young adults with biopsy-proven FSGS (9 cases) or minimal change disease (1 case). The mean age at enrollment was 16.2 years (range 2-30). The workflow did not require referral to external genetics clinics but was conducted entirely during the nephrology standard-of-care appointments. The total turn-around-time from enrollment to return-of-results and clinical decision averaged 21.8 days (12.4 for GS), which is well within a time frame that allows clinically relevant treatment decisions. A monogenic or APOL1-related form of kidney disease was diagnosed in 5 of 10 patients. The genetic findings resulted in a rectified diagnosis in 6 patients. Both positive and negative GS findings determined a change in pharmacological treatment. In 3 patients, the results were instrumental for transplant evaluation, donor selection, and the immunosuppressive treatment. All patients and families received genetic counseling. Conclusion: Clinical GS is feasible and can be implemented in real-time in the outpatient care to help guiding clinical management. Additional studies are needed to confirm the cost-effectiveness and broader utility of clinical GS across the phenotypic and demographic spectrum of kidney diseases.

Clinical Predictors and Prognosis of Recurrent IgA Nephropathy in the Kidney Allograft.

Introduction: Although IgA nephropathy (IgAN) is the most common recurrent glomerulonephritis encountered in the kidney allograft, the clinical and immunogenetic characteristics remain poorly understood. We sought to study determinants and prognosis of recurrent IgAN with special focus on HLA antigens. Materials and Methods: Between 2005 and 2019, we identified 282 transplanted patients with failure secondary to IgAN from two North American and one European Medical Centers, including 80 with recurrent IgAN and 202 without recurrence. Prevalence of HLA antigens was compared to external healthy controls of European ancestry (n=15,740). Graft survival was assessed by Kaplan-Meier method and log rank test. Cox proportional hazards were used for multivariable analyses. Results: Compared to external controls of European ancestry, kidney transplant recipients of European ancestry with kidney failure secondary to IgAN had higher frequency of HLA-DQ5 (42% vs. 30%, OR=1.68, P=0.002) and lower frequency of HLA-DR15 (15% vs. 28%, OR=0.46, P<0.001) and HLA-DQ6 (32% vs. 45%, OR=0.59, P=0.003); however, the frequency of these HLA antigens were similar in recurrent versus non-recurring IgAN. Younger recipient age at transplantation was an independent predictor of recurrence. HLA-matching was an independent predictor for recurrent IgAN only in recipients of living-related but not deceased or living unrelated transplants. Recurrent IgAN was an independent predictor of allograft failure, along with acute rejection. In patients with recurrent IgAN, serum creatinine at biopsy, degree of proteinuria, and concurrent acute rejection were associated with inferior allograft survival. Discussion/ Conclusion: Recurrent IgAN negatively affects allograft survival. Younger recipient age at transplantation is an independent predictor of recurrent IgAN, while the presence of HLA antigens associated with IgAN in the native kidney and HLA-matching in recipients of deceased or living unrelated transplants are not.

Novel approaches beyond standard immunofluorescence for kidney biopsies.

PURPOSE OF REVIEW: Immunofluorescence on frozen tissue (IF-F) utilizing antibodies against immunoglobulin (Ig) heavy and light chains (IgA, IgG and IgM, kappa and lambda) and components of classical and alternative complement pathways (C1q, C3c and C4) is the standard of renal pathology. However, conventional IF-F has limitations, particularly in nephropathies associated with organized and/or monoclonal Ig deposits. This review will discuss new applications of established methods beyond conventional IF-F and recent novel immunohistochemical methods. RECENT FINDINGS: The combined application of paraffin immunofluorescence (IF-P) and IgG subtype staining excluded monotypic deposits in 62-66% of DNA J homolog subfamily B member 9-associated fibrillary glomerulonephritis (FGN) with apparent monotypic deposits by IF-F, whereas IF-P unmasks IgG deposits in a subset of cases of immunotactoid glomerulopathy. A novel IF technique targeting epitopes at the junction of the Ig heavy and light chains was introduced and unmasked polytypic deposits in a subset of glomerulonephritis with apparent monotypic deposits on IF-F. A recent study described the successful application of co-detection by indexing (CODEX) multiplexed IF to visualize more than a dozen target antigens within a single kidney tissue section. Finally, immunohistochemical protocols for detection of the novel antigens in membranous nephropathy have already entered the clinical practice of renal pathology. SUMMARY: Novel ancillary techniques in renal pathology have the potential to significantly enhance our ability to evaluate renal biopsies.

De-novo Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Following the mRNA-1273 (Moderna) Vaccine for COVID-19.

Antineutrophil cytoplasmic antibody (ANCA) is a systemic autoimmune disorder characterized by antibodies directed against small- and moderate-sized vessels. While there are few reported cases of autoimmune illnesses associated with influenza vaccination, two cases of de-novo anti-proteinase (PR3) ANCA-associated pauci immune glomerulonephritis are reported after the mRNA-1273 coronavirus disease 2019 (COVID-19) vaccine. Here, we report the third case of ANCA-associated glomerulonephritis after the mRNA-1273 COVID-19 vaccine. Our patient presented with acute kidney injury and sub-nephrotic proteinuria four days after receiving the second dose of the COVID vaccine. He was found to have elevated c-ANCA and anti-PR3 antibodies. Renal biopsy confirmed focal necrotizing and diffuse crescentic glomerulonephritis. He was diagnosed with pauci immune glomerulonephritis. The patient achieved remission 10 weeks after the diagnosis with successful treatment.

Longitudinal Outcomes of COVID-19-Associated Collapsing Glomerulopathy and Other Podocytopathies.

BACKGROUND: The long-term outcome of COVID-19-associated collapsing glomerulopathy is unknown. METHODS: We retrospectively identified 76 native kidney biopsies from patients with history of COVID-19 between March 2020 and April 2021. Presenting and outcome data were obtained for all 23 patients with collapsing glomerulopathy and for seven patients with noncollapsing podocytopathies. We performed APOL1 genotyping by Sanger sequencing, immunostaining for spike and nucleocapsid proteins, and in situ hybridization for SARS-CoV-2. RESULTS: The 23 patients with COVID-19-associated collapsing glomerulopathy were median age 57 years (range, 35-72), included 16 men, and were predominantly (91%) Black. Severity of COVID-19 was mild or moderate in most (77%) patients. All but one patient presented with AKI, 17 had nephrotic-range proteinuria, and six had nephrotic syndrome. Fourteen (61%) patients required dialysis at presentation. Among 17 patients genotyped, 16 (94%) were high-risk APOL1. Among 22 (96%) patients with median follow-up at 155 days (range, 30-412), 11 (50%) received treatment for COVID-19, and eight (36%) received glucocorticoid therapy for podocytopathy. At follow-up, 19 (86%) patients were alive, and 15 (68%) were dialysis free, including seven of 14 who initially required dialysis. The dialysis-free patients included 64% (seven of 11) of those treated for COVID-19 and 75% (six of eight) of those treated with glucocorticoids for podocytopathy. Overall, 36% achieved partial remission of proteinuria, 32% had no remission, and 32% reached combined end points of ESKD or death. Viral infection of the kidney was not detected. CONCLUSIONS: Half of 14 patients with COVID-19-associated collapsing glomerulopathy requiring dialysis achieved dialysis independence, but the long-term prognosis of residual proteinuric CKD remains guarded, indicating a need for more effective therapy.

Kidney allograft biopsy findings after COVID-19.

COVID-19 has been associated with acute kidney injury and published reports of native kidney biopsies have reported diverse pathologies. Case series directed specifically to kidney allograft biopsy findings in the setting of COVID-19 are lacking. We evaluated 18 kidney transplant recipients who were infected with SARS-CoV-2 and underwent allograft biopsy. Patients had a median age of 55 years, six were female, and five were Black. Fifteen patients developed COVID-19 pneumonia, of which five required mechanical ventilation. Notably, five of 11 (45%) biopsies obtained within 1 month of positive SARS-CoV-2 PCR showed acute rejection (four with arteritis, three of which were not associated with reduced immunosuppression). The remaining six biopsies revealed podocytopathy (n = 2, collapsing glomerulopathy and lupus podocytopathy), acute tubular injury (n = 2), infarction (n = 1), and transplant glomerulopathy (n = 1). Biopsies performed >1 month after positive SARS-CoV-2 PCR revealed collapsing glomerulopathy (n = 1), acute tubular injury (n = 1), and nonspecific histologic findings (n = 5). No direct viral infection of the kidney allograft was detected by immunohistochemistry, in situ hybridization, or electron microscopy. On follow-up, two patients died and most patients showed persistent allograft dysfunction. In conclusion, we demonstrate diverse causes of kidney allograft dysfunction after COVID-19, the most common being acute rejection with arteritis.

Heavy and light chains all at once: A new immunofluorescence technique to evaluate monoclonal immunoglobulin deposits.

Tools to identify monoclonal Ig deposits within tissue specimens include immunofluorescence (IF) staining on frozen tissue for Ig heavy chains and light chains, pronase IF to unmask monoclonal Ig deposits not seen by IF staining on frozen tissue, and IF staining for IgG subclasses (IgG1-IgG4). In this issue of Kidney International, a novel diagnostic tool is introduced: IF staining for conformational epitopes at the junction of the Ig heavy chains and light chains. This technique has the potential to significantly enhance our ability to evaluate apparent monoclonal forms of renal disease.

The clinical significance of receiving a kidney allograft from deceased donor with chronic histologic changes.

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.