A molecular single-cell lung atlas of lethal COVID-19.

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection1,2, but the host response at the lung tissue level is poorly understood. Here we performed single-nucleus RNA sequencing of about 116,000 nuclei from the lungs of nineteen individuals who died of COVID-19 and underwent rapid autopsy and seven control individuals. Integrated analyses identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, thereby providing insight into the biology of lethal COVID-19. The lungs from individuals with COVID-19 were highly inflamed, with dense infiltration of aberrantly activated monocyte-derived macrophages and alveolar macrophages, but had impaired T cell responses. Monocyte/macrophage-derived interleukin-1ß and epithelial cell-derived interleukin-6 were unique features of SARS-CoV-2 infection compared to other viral and bacterial causes of pneumonia. Alveolar type 2 cells adopted an inflammation-associated transient progenitor cell state and failed to undergo full transition into alveolar type 1 cells, resulting in impaired lung regeneration. Furthermore, we identified expansion of recently described CTHRC1+ pathological fibroblasts3 contributing to rapidly ensuing pulmonary fibrosis in COVID-19. Inference of protein activity and ligand-receptor interactions identified putative drug targets to disrupt deleterious circuits. This atlas enables the dissection of lethal COVID-19, may inform our understanding of long-term complications of COVID-19 survivors, and provides an important resource for therapeutic development.

Clinicopathologic Characteristics of Crystalglobulin-Induced Nephropathy: A Case Series.

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.

The pathologic spectrum of adenovirus nephritis in the kidney allograft.

Adenovirus nephritis (ADVN) is a rare and understudied complication of kidney transplantation. Unlike BK virus nephropathy (BKVN), our knowledge of clinicopathologic manifestations of ADVN remains rudimentary and essentially limited to case reports. To expand on this, we retrospectively studied 11 kidney transplant recipients with ADVN and compared their allograft biopsies to 33 kidney transplant recipients with BKVN using conventional microscopy and the 770 gene Nanostring Banff Human Organ Transplant Profiling Panel. Patients with ADVN had a median age of 44 years, were predominantly male, and developed ADVN at a median of 31 months post-transplantation. Eight patients presented with fever and ten had hematuria. The most common histologic manifestations included granulomas (82%), tubulocentric inflammation (73%), and tubular degenerative changes consistent with acute tubular necrosis (73%). During a median follow-up of 55 months after biopsy, three patients developed allograft failure from subsequent acute rejection. All seven patients with available follow-up PCR showed resolution of viremia at a median of 30 days after diagnosis. Compared to BKVN, ADVN demonstrated more granulomas and less tubulointerstitial scarring. On follow-up, patients with ADVN had more rapid clearance of viral DNA from plasma. Transcriptomic analyses showed that ADVN had increased expression of several pro-inflammatory transcriptomes, mainly related to innate immunity, was associated with increased expression of transcripts with inhibitory effects on inflammatory response and showed higher enrichment with neutrophils, which can cause aggressive but short-lasting damage. Thus, we demonstrate that, despite its association with aggressive neutrophil-rich inflammation, ADVN does not often lead to allograft failure. Hence, preventing subsequent acute rejection following resolution of ADVN may improve allograft survival.

Mayo Clinic consensus report on membranous nephropathy: proposal for a novel classification.

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.

Proliferative Glomerulonephritis With Hidden Monotypic IgG3κ Deposits: A Case Report.

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.

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.

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.

Anti-neutrophil cytoplasmic antibody associated glomerulonephritis complicating treatment with hydralazine.

Hydralazine, a widely used therapy for hypertension and heart failure, can elicit autoimmune disease, including anti-neutrophil cytoplasmic antibody associated glomerulonephritis (ANCA-GN). We identified 80 cases of ANCA-GN complicating treatment with hydralazine, accounting for 4.3% (80/1858 biopsies) of ANCA-GN diagnosed between 2006 and 2019. Over three-fourths of patients were on hydralazine for at least one year, with mean daily dose of approximately 250 mg/day. ANCA testing revealed p-ANCA/myeloperoxidase-ANCA seropositivity in 98%, including 39% with dual p-ANCA/myeloperoxidase-ANCA and cANCA/anti-protinase 3-ANCA positivity, often accompanied by anti-nuclear antibody (89%), anti-histone antibody (98%), and hypocomplementemia (58%). Kidney biopsy revealed necrotizing and crescentic glomerulonephritis, similar to primary ANCA-GN, but significantly less frequently pauci-immune (77 vs. 100%) and more commonly associated with mesangial hypercellularity (30 vs. 5%), electron dense deposits (62 vs. 20%), and endothelial tubuloreticular inclusions (11 vs. 0%); all significant differences. On follow-up, 42 of 51 patients received induction immunosuppression: 19 reached the combined end-points of kidney failure or death and 32 had mean creatinine of 1.49 mg/dL at last follow-up. Thus, hydralazine-associated ANCA-GN often exhibits overlapping clinical and pathologic features of mild immune complex glomerulonephritis resembling lupus nephritis. With discontinuation of hydralazine and immunosuppression, outcomes are similar to primary ANCA-GN.

The clinicopathologic spectrum of segmental membranous glomerulopathy.

Membranous glomerulopathy (MGN) is characterized by global subepithelial immune deposits that stain most intensely by immunofluorescence for IgG. Here we describe the clinical and pathologic findings in a cohort of patients with MGN in which, by definition, only segmental immune deposits are present. This rare variant, termed segmental MGN (sMGN), is poorly characterized. We retrospectively identified all patients with sMGN diagnosed at Columbia University from January 2010 to October 2018, excluding those with systemic lupus erythematosus. Data on presenting features, pathologic findings, and outcomes were collected. Fifty cases of sMGN were identified, representing 2.5% of MGN. In 21 of 50 biopsies, there was an alternative, predominant disease process. The remaining 29 patients with isolated sMGN had a median creatinine of 0.97 mg/dl, median 24-hour urine protein 3.1 g/day, and 32% had nephrotic syndrome. Staining for NELL-1 (a protein kinase C binding protein) was positive in five of 17 cases. Staining for PLA2R, THSD7A, and exostosin 1 (autoantigens in primary MGN) was negative in all biopsies evaluated. Ultrastructural evaluation revealed predominantly early stage sMGN (stage 1 or 1-2 in 14/29). Follow-up was available for 21 of the 29 patients with isolated sMGN (median 12 months), including seven who received immunosuppression (primarily glucocorticoids). During follow-up, 86% had stable/improved kidney function and 45% achieved complete while 15% achieved partial remission. Among the 15 patients with isolated sMGN without full nephrotic syndrome, only two received immunosuppression; nonetheless, 50% achieved complete while 21% achieved partial remission. Thus, sMGN is a rare PLA2R-negative variant of MGN with 29% NELL-1 positivity and favorable prognosis, even in the absence of immunosuppressive treatment.

Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants.

Immunotactoid glomerulopathy (ITG) is a rare form of glomerulonephritis for which our understanding is limited to case reports and small case series. Herein we describe the clinical, pathologic, and outcome characteristics of 73 patients with ITG who typically presented with proteinuria, hematuria, and renal insufficiency. Hematologic disorders were present in 66% of patients, including lymphoma in 41% (mainly chronic lymphocytic leukemia/small lymphocytic lymphoma), monoclonal gammopathy in 20%, and multiple myeloma in 6%. Light microscopy revealed endocapillary proliferative (35%), membranoproliferative (29%) and membranous (29%) patterns of glomerular involvement. Electron microscopy revealed characteristic microtubular deposits with a diameter of 14-60 nm, hollow cores, frequent parallel alignment, and a predominant distribution outside of the lamina densa of the glomerular basement membrane. Importantly, immunofluorescence revealed IgG-dominant staining which was light chain and IgG subclass restricted in 67% of cases, indicating monoclonal composition. This finding was used to distinguish monoclonal and polyclonal variants of ITG. As compared to polyclonal, monoclonal ITG had a higher incidence of lymphoma (53% vs. 11%), multiple myeloma (8% vs. 0), and monoclonal gammopathy (22% vs. 16%). Monoclonal ITG was more commonly treated with clone-directed therapy, which was associated with more frequent remission and less frequent end stage kidney disease. Thus, a third of ITG cases are polyclonal but a quarter of these cases are associated with hematologic conditions, underscoring the need for hematologic evaluation in all patients with ITG. Hence, based on these distinctions, ITG should be subclassified into monoclonal and polyclonal variants. Prognosis of ITG is good if the underlying hematologic condition is treated.

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.

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.

Concurrent Anti-Glomerular Basement Membrane Antibody Disease and Membranous Nephropathy: A Case Series.

RATIONALE & OBJECTIVE: Anti-glomerular basement membrane (GBM) disease is a rapidly progressive glomerulonephritis which, in some instances, occurs concurrently with other diseases such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Rarely, it also occurs with membranous nephropathy (MN). We report a series of such patients, characterizing their long-term follow up. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Twelve patients referred to 1 medical center between 2001 and 2019 with anti-GBM disease and MN whose clinical characteristics and course were described. RESULTS: Patients' ages ranged from 20 to 81 years old, and all presented with severe acute kidney injury requiring dialysis on presentation or shortly thereafter. Only 1 patient had pulmonary findings on presentation. The predominant pathology was crescentic and necrotizing glomerulonephritis with linear staining for immunoglobulin G along the GBM associated with epimembranous electron-dense immune-type deposits. All 11 patients who were tested had significant titers of anti-GBM antibodies, but only 1 of the 5 tested for phospholipase A2 receptor (PLA2R) on biopsy was positive. Eight patients received therapy with cyclophosphamide, prednisone, and plasmapheresis; 2 patients with prednisone and plasmapheresis; and 2 with rituximab-based regimens. Progression to a requirement for kidney replacement therapy occurred in all 12 patients, but 2 patients later recovered kidney function. Recurrence of anti-GBM disease did not occur for any of the patients studied. LIMITATIONS: Incomplete testing for PLA2R in biopsy and serum, limited sample size, and lack of uniform treatment regimen. CONCLUSIONS: In this case series, the presentation of concurrent anti-GBM disease and MN was characterized by rapidly progressive glomerulonephritis and poor kidney outcomes. These findings suggest possible value from earlier diagnosis and the need for identification of more effective treatment regimens.

Postmortem Kidney Pathology Findings in Patients with COVID-19.

BACKGROUND: AKI is common among hospitalized patients with coronavirus disease 2019 (COVID-19) and is an independent risk factor for mortality. Although there are numerous potential mechanisms underlying COVID-19-associated AKI, our current knowledge of kidney pathologic findings in COVID-19 is limited. METHODS: We examined the postmortem kidneys from 42 patients who died of COVID-19. We reviewed light microscopy findings in all autopsies and performed immunofluorescence, electron microscopy, and in situ hybridization studies for SARS-CoV-2 on a subset of samples. RESULTS: The cohort had a median age of 71.5 years (range, 38-97 years); 69% were men, 57% were Hispanic, and 73% had a history of hypertension. Among patients with available data, AKI developed in 31 of 33 patients (94%), including 6 with AKI stage 1, 9 with stage 2, and 16 with stage 3. The predominant finding correlating with AKI was acute tubular injury. However, the degree of acute tubular injury was often less severe than predicted for the degree of AKI, suggesting a role for hemodynamic factors, such as aggressive fluid management. Background changes of hypertensive arterionephrosclerosis and diabetic glomerulosclerosis were frequent but typically mild. We identified focal kidney fibrin thrombi in 6 of 42 (14%) autopsies. A single Black patient had collapsing FSGS. Immunofluorescence and electron microscopy were largely unrevealing, and in situ hybridization for SARS-CoV-2 showed no definitive positivity. CONCLUSIONS: Among a cohort of 42 patients dying with COVID-19, autopsy histologic evaluation revealed acute tubular injury, which was typically mild relative to the degree of creatinine elevation. These findings suggest potential for reversibility upon resolution of SARS-CoV-2 infection.

Kidney Biopsy Findings in Patients with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is thought to cause kidney injury by a variety of mechanisms. To date, pathologic analyses have been limited to patient reports and autopsy series. METHODS: We evaluated biopsy samples of native and allograft kidneys from patients with COVID-19 at a single center in New York City between March and June of 2020. We also used immunohistochemistry, in situ hybridization, and electron microscopy to examine this tissue for presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RESULTS: The study group included 17 patients with COVID-19 (12 men, 12 black; median age of 54 years). Sixteen patients had comorbidities, including hypertension, obesity, diabetes, malignancy, or a kidney or heart allograft. Nine patients developed COVID-19 pneumonia. Fifteen patients (88%) presented with AKI; nine had nephrotic-range proteinuria. Among 14 patients with a native kidney biopsy, 5 were diagnosed with collapsing glomerulopathy, 1 was diagnosed with minimal change disease, 2 were diagnosed with membranous glomerulopathy, 1 was diagnosed with crescentic transformation of lupus nephritis, 1 was diagnosed with anti-GBM nephritis, and 4 were diagnosed with isolated acute tubular injury. The three allograft specimens showed grade 2A acute T cell-mediated rejection, cortical infarction, or acute tubular injury. Genotyping of three patients with collapsing glomerulopathy and the patient with minimal change disease revealed that all four patients had APOL1 high-risk gene variants. We found no definitive evidence of SARS-CoV-2 in kidney cells. Biopsy diagnosis informed treatment and prognosis in all patients. CONCLUSIONS: Patients with COVID-19 develop a wide spectrum of glomerular and tubular diseases. Our findings provide evidence against direct viral infection of the kidneys as the major pathomechanism for COVID-19-related kidney injury and implicate cytokine-mediated effects and heightened adaptive immune responses.

The spectrum of kidney biopsy findings in HIV-infected patients in the modern era.

HIV-associated kidney disease is evolving rapidly. Few North American studies have addressed modern trends and none has applied the 2018 Kidney Disease Improving Global Outcomes (KDIGO) pathologic classification. Therefore we performed a retrospective clinical-pathologic analysis of all HIV-positive patients with kidney biopsy interpreted at Columbia University from 2010-2018 using the KDIGO classification. The biopsy cohort of 437 HIV-positive patients had median age 53 years, including 66% males, 80% on anti-retroviral therapy, 57% with hypertension, 31% with diabetes, 27% with hepatitis C and 6% with hepatitis B co-infections. Race, known in 308 patients, included 58% black, 25% white and 17% Hispanic. Pathologic diagnoses were surprisingly diverse. Immune complex glomerulonephritis (ICGN) and diabetic nephropathy each outnumbered HIV-associated nephropathy, followed by tenofovir nephrotoxicity, FSGS- not otherwise specified (NOS) and global sclerosis (NOS). HIV-associated nephropathy was the most common disease in patients not on anti-retroviral therapy, and 94% were black. The association of FSGS (NOS) with black race (68%) and anti-retroviral therapy use (77%) suggests some cases may represent attenuated HIV-associated nephropathy. The most common ICGNs were IgA nephropathy and membranous glomerulopathy, both associating with anti-retroviral therapy (over 90%), followed by hepatitis C-associated proliferative ICGN. Among the 16 cases of uncharacterized ICGN lacking identifiable etiology, 69% were not on anti-retroviral therapy, possibly representing true HIV-associated immune complex kidney disease. Dual diseases occurred in 17% of patients, underscoring lesion complexity. Thus, anti-retroviral therapy has shifted the landscape of HIV-associated kidney disease toward diverse ICGN, diabetic nephropathy, and non-collapsing glomerulosclerosis, but has not eradicated HIV-associated nephropathy.

Association of HLA Typing and Alloimmunity With Posttransplantation Membranous Nephropathy: A Multicenter Case Series.

RATIONALE & OBJECTIVES: Posttransplantation membranous nephropathy (MN) represents a rare complication of kidney transplantation that can be classified as recurrent or de novo. The clinical, pathologic, and immunogenetic characteristics of posttransplantation MN and the differences between de novo and recurrent MN are not well understood. STUDY DESIGN: Multicenter case series. SETTING & PARTICIPANTS: We included 77 patients from 5 North American and European medical centers with post-kidney transplantation MN (27 de novo and 50 recurrent). Patients with MN in the native kidney who received kidney allografts but did not develop recurrent MN were used as nonrecurrent controls (n = 43). To improve understanding of posttransplantation MN, we compared de novo MN with recurrent MN and then contrasted recurrent MN with nonrecurrent controls. FINDINGS: Compared with recurrent MN, de novo MN was less likely to be classified as primary MN (OR, 0.04; P < 0.001) and had more concurrent antibody-mediated rejection (OR, 12.0; P < 0.001) and inferior allograft survival (HR for allograft failure, 3.2; P = 0.007). HLA-DQ2 and HLA-DR17 antigens were more common in recipients with recurrent MN compared with those with de novo MN; however, the frequency of these recipient antigens in recurrent MN was similar to that in nonrecurrent MN controls. Among the 93 kidney transplant recipients with native kidney failure attributed to MN, older recipient age (HR per each year older, 1.03; P = 0.02), recipient HLA-A3 antigen (HR, 2.5; P = 0.003), steroid-free immunosuppressive regimens (HR, 2.84; P < 0.001), and living related allograft (HR, 1.94; P = 0.03) were predictors of MN recurrence. LIMITATIONS: Retrospective case series, limited sample size due to rarity of the disease, nonstandardized nature of data collection and biopsies. CONCLUSIONS: De novo and recurrent MN likely represent separate diseases. De novo MN is associated with humoral alloimmunity and guarded outcome. Potential predisposing factors for recurrent MN include recipients who are older, recipient HLA-A3 antigen, steroid-free immunosuppressive regimen, and living related donor kidney.

The spectrum of kidney biopsy findings in patients with morbid obesity.

Morbid obesity, defined as body mass index (BMI) ≥40 kg/m2, affects approximately 8% of United States adults and is a recognized risk factor for chronic kidney disease (CKD). We present the first focused biopsy-based study exploring the range of kidney diseases in this population. Among 3263 native kidney biopsies interpreted at Columbia University in 2017, we identified 248 biopsies from morbidly obese patients. In this cohort with median age of 53.5 years, 56% were female and median BMI was 44.0 kg/m2. Diabetes and hypertension were present in 47% and 81% of patients, respectively. Median estimated glomerular filtration rate (eGFR) was 30 ml/min/1.73 m2, and most patients had nephrotic range proteinuria. Obesity related glomerulopathy (ORG), defined as focal segmental glomerulosclerosis with glomerulomegaly or glomerulomegaly alone, was detected in 73 patients, including 29 with ORG alone and 44 with ORG plus another kidney disease. In contrast, 167 patients had other kidney diseases alone, without ORG, most commonly (in descending order) diabetic nephropathy, acute tubular necrosis, hypertensive nephrosclerosis, IgA nephropathy, membranous nephropathy, and lupus nephritis. In 49% of patients, kidney biopsy yielded a diagnosis predicted to change patient management. The strongest predictor of non-ORG lesions was eGFR <30 ml/min per 1.73 m2, and presentation with nephrotic syndrome or acute kidney injury (with or without background CKD) was more common in non-ORG than ORG. The findings reveal an unexpectedly broad spectrum of kidney pathology beyond metabolic syndrome-associated disorders and highlight the importance of kidney biopsy to guide management and prognosis in the morbidly obese population.

Incidence, management, and outcomes of autoimmune nephropathies following alemtuzumab treatment in patients with multiple sclerosis.

BACKGROUND: Autoimmune disorders including nephropathies have been reported more frequently in alemtuzumab-treated multiple sclerosis (MS) patients than in the general population. OBJECTIVE: Describe instances of autoimmune nephropathy in alemtuzumab-treated MS patients. METHODS: Cases were identified from safety monitoring within the alemtuzumab relapsing-remitting multiple sclerosis (RRMS) clinical development program (CDP) or post-marketing, or following off-label use. RESULTS: As of 16 June 2017, 16 autoimmune nephropathies have occurred following alemtuzumab treatment for MS. The incidence of autoimmune nephropathies was 0.34% within the CDP (5/1485 patients). The five CDP cases (one of anti-glomerular basement membrane (anti-GBM) disease, two of membranous glomerulonephropathy, and two of serum anti-GBM antibody without typical anti-GBM disease) were identified early, responded to conventional therapy (where needed), and had favorable outcomes. Three of 11 cases outside the CDP occurred following off-label alemtuzumab use prior to approval for RRMS and were all anti-GBM disease. Diagnosis was delayed in one of these three cases and another did not receive appropriate treatment; all three cases resulted in end-stage renal failure. All anti-GBM disease cases with documented urinalysis demonstrated prior microscopic hematuria. CONCLUSION: Close monitoring of alemtuzumab-treated MS patients facilitates diagnosis and treatment early in the nephropathy course when preservation of renal function is more likely.