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BACKGROUNDIt is unknown whether the risk of kidney disease progression and failure differs between patients with and without genetic kidney disorders.METHODSThree cohorts were evaluated: the prospective Cure Glomerulonephropathy Network (CureGN) and 2 retrospective cohorts from Columbia University, including 5,727 adults and children with kidney disease from any etiology who underwent whole-genome or exome sequencing. The effects of monogenic kidney disorders and APOL1 kidney-risk genotypes on the risk of kidney failure, estimated glomerular filtration rate (eGFR) decline, and disease remission rates were evaluated along with diagnostic yields and the impact of American College of Medical Genetics secondary findings (ACMG SFs).RESULTSMonogenic kidney disorders were identified in 371 patients (6.5%), high-risk APOL1 genotypes in 318 (5.5%), and ACMG SFs in 100 (5.2%). Family history of kidney disease was the strongest predictor of monogenic disorders. After adjustment for traditional risk factors, monogenic kidney disorders were associated with an increased risk of kidney failure (hazard ratio [HR] = 1.72), higher rate of eGFR decline (-3.06 vs. 0.25 mL/min/1.73 m2/year), and lower risk of complete remission (odds ratioNot achieving CR = 5.25). High-risk APOL1 genotypes were associated with an increased risk of kidney failure (HR = 1.67) and faster eGFR decline (-2.28 vs. 0.25 mL/min/1.73 m2), replicating prior findings. ACMG SFs were not associated with personal or family history of associated diseases, but were predicted to impact care in 70% of cases.CONCLUSIONSMonogenic kidney disorders were associated with an increased risk of kidney failure, faster eGFR decline, and lower rates of complete remission, suggesting opportunities for early identification and intervention based on molecular diagnosis.TRIAL REGISTRATIONNA.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases grants U24DK100845 (formerly UM1DK100845), U01DK100846 (formerly UM1DK100846), U01DK100876 (formerly UM1DK100876), U01DK100866 (formerly UM1DK100866), U01DK100867 (formerly UM1DK100867), U24DK100845, DK081943, RC2DK116690, 2U01DK100876, 1R01DK136765, 5R01DK082753, and RC2-DK122397; NephCure Kidney International; Department of Defense Research Awards PR201425, W81XWH-16-1-0451, and W81XWH-22-1-0966; National Center for Advancing Translational Sciences grant UL1TR001873; National Library of Medicine grant R01LM013061; National Human Genome Research Institute grant 2U01HG008680.
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Apolipoproteína L1 , Tasa de Filtración Glomerular , Insuficiencia Renal , Humanos , Masculino , Femenino , Adulto , Apolipoproteína L1/genética , Persona de Mediana Edad , Insuficiencia Renal/genética , Factores de Riesgo , Niño , Estudios Retrospectivos , Adolescente , Estudios Prospectivos , Enfermedades Renales/genéticaRESUMEN
Introduction: Methamphetamine (METH) is one of the most used drugs of abuse worldwide. However, there are few reports and series examining the toxic kidney effects of METH, and associated histopathological changes are not well-described. Methods: We retrospectively identified 112 patients with a history significant for METH abuse, of whom 62 were using METH-only and 60 were using METH plus other drugs of abuse. Results: In the METH-only cohort, the mean age was 41 years (interquartile range [IQR]: 33-49) and most (76%) were male. Almost all cases (97%) showed evidence of kidney dysfunction at the time of biopsy. Of the cases, 65% had proteinuria, of which 53% were nephrotic range and 10% had nephrotic syndrome. The most common biopsy diagnosis was acute tubular necrosis (ATN) (66%), of which 19% had myoglobin casts; followed by focal segmental glomerulosclerosis (FSGS) in 53% (not otherwise specified [NOS] in 76% and collapsing FSGS [cFSGS] in 18%). Biopsy findings also include tubulointerstitial nephritis (TIN) (37%), thrombotic microangiopathy (TMA) (24%), and diabetic glomerulosclerosis (DG) (31%). Glomerulonephritis (GN) was identified in one-third of cases, the most common of which were infection-related GN (IRGN) (15%) and IgA nephropathy (IgAN) (11%). Of those with GN, 64% had underlying infection. Of interest, there was increased association for myoglobinuric ATN in those with concurrent ethanol-abuse (P = 0.002). Moreover, the METH-only patients were more likely to have DG compared to those with multiple substance-use (P = 0.01). More than half of the patients demonstrated at least moderate to severe tubulointerstitial scarring and marked hypertensive vascular disease. Conclusion: Most patients with METH-use present with acute kidney injury (AKI) and often have proteinuria associated with a wide spectrum of renal pathology.
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Recent progress in glomerular immune complex and complement-mediated diseases have refined diagnostic categories and informed mechanistic understanding of disease development in pediatric patients. Herein, we discuss selected advances in 3 categories. First, membranous nephropathy antigens are increasingly utilized to characterize disease in pediatric patients and include phospholipase A2 receptor (PLA2R), Semaphorin 3B (Sema3B), neural epidermal growth factor-like 1 (NELL1), and protocadherin FAT1, as well as the lupus membranous-associated antigens exostosin 1/2 (EXT1/2), neural cell adhesion molecule 1 (NCAM1), and transforming growth factor beta receptor 3 (TGFBR3). Second, we examine advances in techniques for paraffin and light chain immunofluorescence (IF), including the former's function as a salvage technique and their necessity for diagnosis in adolescent cases of membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) and proliferative glomerulonephritis with monotypic Ig deposits (PGNMID), respectively. Finally, progress in understanding the roles of complement in pediatric glomerular disease is reviewed, with specific attention to overlapping clinical, histologic, and genetic or functional alternative complement pathway (AP) abnormalities among C3 glomerulopathy (C3G), infection-related and post-infectious GN, "atypical" post-infectious GN, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN), and atypical hemolytic uremic syndrome (aHUS).
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The steps governing healing with or without fibrosis within the same microenvironment are unclear. After acute kidney injury (AKI), injured proximal tubular epithelial cells activate SOX9 for self-restoration. Using a multimodal approach for a head-to-head comparison of injury-induced SOX9 lineages, we identified a dynamic SOX9 switch in repairing epithelia. Lineages that regenerated epithelia silenced SOX9 and healed without fibrosis (SOX9on-off). By contrast, lineages with unrestored apicobasal polarity maintained SOX9 activity in sustained efforts to regenerate, which were identified as a SOX9on-on Cadherin6pos cell state. These reprogrammed cells generated substantial single-cell WNT activity to provoke a fibroproliferative response in adjacent fibroblasts, driving AKI to chronic kidney disease. Transplanted human kidneys displayed similar SOX9/CDH6/WNT2B responses. Thus, we have uncovered a sensor of epithelial repair status, the activity of which determines regeneration with or without fibrosis.
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Lesión Renal Aguda , Túbulos Renales Proximales , Riñón , Insuficiencia Renal Crónica , Factor de Transcripción SOX9 , Animales , Humanos , Ratones , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Células Epiteliales , Fibrosis , Riñón/patología , Regeneración , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Factor de Transcripción SOX9/genética , Túbulos Renales Proximales/citología , Túbulos Renales Proximales/metabolismoRESUMEN
OBJECTIVES: Alpha-mannosidosis is a rare genetic lysosomal storage condition leading to the systemic buildup of oligomannoside. Clinical presentation and associated conditions, as well as the full extent of histopathologic changes associated with this disease process, are not fully understood. CASE PRESENTATION: We present the case of an 8-year-1-month old patient with persistent anemia and who was initially diagnosed with Celiac disease before ultimately being diagnosed with alpha-mannosidosis. As part of his diagnostic work-up, duodenal and bone marrow biopsies were examined by pathology. Duodenal biopsies showed foamy plasma cells expanding the lamina propria which triggered a workup for a genetic storage disease; features suggestive of Celiac disease which resolved on gluten-free diet were also noted by pathology. Bone marrow analysis via electron microscopy showed cytoplasmic granules and inclusions in multiple immune cell lines. CONCLUSIONS: Alpha-mannosidosis can occur with Celiac disease and milder forms may only be suspected from incidental pathology findings. The ultrastructural bone marrow findings from this case, the first to be reported from human, show numerous disease-associated changes in multiple immune cell lines whose contribution to disease-associated immunodeficiency is unclear.
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Enfermedad Celíaca , Enfermedades por Almacenamiento Lisosomal , alfa-Manosidosis , Humanos , Lactante , alfa-Manosidosis/diagnóstico , alfa-Manosidosis/complicaciones , alfa-Manosidosis/genética , Microscopía , Enfermedad Celíaca/complicaciones , Enfermedades por Almacenamiento Lisosomal/diagnósticoRESUMEN
Introduction: Cure Glomerulonephropathy (CureGN) is an observational cohort study of patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), or IgA nephropathy. We developed a conventional, consensus-based scoring system to document pathologic features for application across multiple pathologists and herein describe the protocol, reproducibility, and correlation with clinical parameters at biopsy. Methods: Definitions were established for glomerular, tubular, interstitial, and vascular lesions evaluated semiquantitatively using digitized light microscopy slides and electron micrographs, and reported immunofluorescence. Cases with curated pathology materials as of April 2019 were scored by a randomly assigned pathologist, with at least 10% of cases scored by a second pathologist. Scoring reproducibility was assessed using Gwet's agreement coefficient (AC)1 statistic and correlations with clinical variables were performed. Results: Of 800 scored biopsies (134 MCD, 194 FSGS, 206 MN, 266 IgA), 94 were scored twice (11.8%). Of 60 pathology features, 46 (76.7%) demonstrated excellent (AC1>0.8), and 12 (20.0%) had good (AC1 0.6-0.8) reproducibility. Mesangial hypercellularity scored as absent, focal, or diffuse had moderate reproducibility (AC1 = 0.58), but good reproducibility (AC1 = 0.71) when scored as absent or focal versus diffuse. The percent glomeruli scored as no lesions had fair reproducibility (AC1 = 0.34). Strongest correlations between pathologic features and clinical characteristics at biopsy included interstitial inflammation, interstitial fibrosis, and tubular atrophy with estimated glomerular filtration rate, foot process effacement with urine protein/creatinine ratio, and active crescents with hematuria. Conclusions: Most scored pathology features showed excellent reproducibility, demonstrating consistency for these features across multiple pathologists. Correlations between certain pathologic features and expected clinical characteristics show the value of this approach for future studies on clinicopathologic correlations and biomarker discovery.
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Background: Fabry disease (FD) is an X-linked disorder due to a pathogenic variant of the GLA gene that codes for the alpha-galactosidase enzyme. The reduced or absent activity of the enzyme results in lysosomal accumulation of globotriosylceramide and its derivative, globotriaosylsphingosine, in a variety of cells, leading to a variety of complications including cardiac, renal, and cerebrovascular disorders. Early diagnosis is critically important for the selection of therapeutic treatments, which are essential for improving outcomes. Here we present a case of FD diagnosed at the time of end-stage kidney disease presentation. Summary: A 40-year-old man with a history of seizures presented with increased serum creatinine, nephrotic rage proteinuria, and new-onset hypertension. A renal biopsy revealed numerous, whorled, and lamellated cytoplasmic inclusions in podocytes, glomerular peritubular capillary endothelial cells, mesangial cells, arterial myocytes, and interstitial macrophages. Ultrastructural analysis confirmed the presence of glycosphingolipid inclusions and enlarged lysosomes packed with multi-lamellated structures ("zebra" bodies). The findings were suggestive of a lysosomal storage disorder, and testing for alpha-galactosidase A levels revealed near-absent enzyme activity, confirming the diagnosis of advanced FD. Key Messages: The diagnosis of FD can be challenging as the manifestations of the disease are nonspecific, and patients can present early with classical symptoms or late with non-classical patterns of involvement. We will discuss strategies to identify the disorder early by reviewing the classical and non-classical presentations and further outline currently available and potential future treatment options.
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Introduction: Membranous nephropathy (MN) is a common cause of adult nephrotic syndrome in the USA. The typical ultrastructural finding is of global uniformly dense subepithelial electron-dense immune complex deposits along glomerular basement membranes. However, early reports described deposits with a unique microspherular substructure. There was variability in what was identified as microspherular, sometimes overlapping with other entities such as podocyte infolding glomerulopathy. Currently, the nature, composition, and clinical significance of these microspherular deposits (MSDs) remain unknown. Method: We report the clinicopathologic features of a series of MN cases with MSD, with detailed ultrastructural characterization as well as PLA2R and THSD7A immunohistochemical and IgG subclass-staining characteristics. The proportion of MSD to overall deposits is segregated into two groups: global MSD with >50% MSD (n = 14) and segmental MSD with <50% (n = 5). Results: The size and appearance of the microspherules were nearly identical in global and segmental MSD groups (mean diameter of 77.9 nm and 77.2 nm, respectively), with subepithelial (n = 19) or intramembranous (n = 12) distributions in all cases. Mesangial MSDs (n = 5) were only found in the global MSD group. The majority of biopsies (86% of global MSD and 100% of segmental MSD) were Ehrenreich-Churg stage 2 or above; early stage 1 was only observed in the global MSD group. All but 3 cases were PLA2R/THSD7A double negative; 1 THSD7A positive in global MSD and 2 PLA2R positive in segmental MSD. IgG1 was the dominant subclass in the global MSD group, and IgG4 was dominant in the segmental MSD group, including the 2 PLA2R-positive cases. Conclusion: The findings suggest that MSDs are more commonly associated with secondary MN. This case series is the largest to date, and the findings may yield etiologic and prognostic information on this rare but unique subset of MN and provide a well-characterized cohort of cases for future studies.
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Anti-glomerular basement membrane (GBM) antibody nephritis is defined by linear immunofluorescence staining of GBM by immunoglobulin G (IgG), typically associated with GBM rupture, fibrinoid necrosis, and crescent formation. Clinically, the patients present with rapidly worsening renal function, often with hematuria. Typical renal pathologic findings include necrotizing and crescentic glomerulonephritis. In contrast, thrombotic microangiopathy (TMA) is characterized by microvascular thrombosis, which can also lead to acute kidney injury. Thrombotic microangiopathy is associated with some systemic diseases and has characteristic clinical features of microangiopathic hemolytic anemia, platelet consumption, and multiple organ failure. Anti-GBM nephritis associated with TMA has rarely been reported. We describe an unusual case of atypical anti-GBM disease without crescent formation or necrosis but with light microscopic and ultrastructural features consistent with endothelial cell injury and glomerular-limited TMA.
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Glomerulonefritis , Nefritis , Púrpura Trombocitopénica Trombótica , Humanos , Glomerulonefritis/complicaciones , Glomerulonefritis/patología , Necrosis , Membrana Basal/patologíaRESUMEN
SIGNIFICANCE STATEMENT: Syphilis is a common worldwide sexually transmitted infection. Proteinuria may occur in patients with syphilis. Membranous nephropathy (MN) is the most common cause of proteinuria in syphilis. The target antigen of MN in syphilis is unknown. This study shows that MN in syphilis is associated with a novel target antigen called neuron-derived neurotrophic factor (NDNF). NDNF-associated MN has distinctive clinical and pathologic manifestations and NDNF appears to be the target antigen in syphilis-associated MN. BACKGROUND: Syphilis is a common sexually transmitted infection. Membranous nephropathy (MN) is a common cause of proteinuria in syphilis. The target antigen is not known in most cases of syphilis-associated MN. METHODS: We performed laser microdissection of glomeruli and mass spectrometry (MS/MS) in 250 cases (discovery cohort) of phospholipase A2 receptor-negative MN to identify novel target antigens. This was followed by immunohistochemistry/confocal microscopy to localize the target antigen along the glomerular basement membrane (GBM). Western blot analyses using IgG eluted from frozen biopsy tissue were performed to detect binding to target antigen. RESULTS: MS/MS studies of the discovery cohort revealed high total spectral counts of a novel protein, neuron-derived neurotrophic factor (NDNF), in three patients: one each with syphilis and hepatitis B, HIV (syphilis status not known), and lung tumor. Next, MS/MS studies of five cases of syphilis-MN (validation cohort) confirmed high total spectral counts of NDNF (average 45±20.4) in all (100%) cases. MS/MS of 14 cases of hepatitis B were negative for NDNF. All eight cases of NDNF-associated MN were negative for known MN antigens. Electron microscopy showed stage I MN in all cases, with superficial and hump-like deposits without GBM reaction. IgG1 was the dominant IgG subtype on MS/MS and immunofluorescence microscopy. Immunohistochemistry/confocal microscopy showed granular staining and colocalization of NDNF and IgG along GBM. Western blot analyses using eluate IgG of NDNF-MN showed binding to both nonreduced and reduced NDNF, while IgG eluate from phospholipase A2 receptor-MN showed no binding. CONCLUSION: NDNF is a novel antigenic target in syphilis-associated MN.
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Glomerulonefritis Membranosa , Hepatitis B , Sífilis , Humanos , Receptores de Fosfolipasa A2 , Espectrometría de Masas en Tándem , Factores de Crecimiento Nervioso , Neuronas , Membrana Basal Glomerular , Inmunoglobulina GAsunto(s)
Amiloidosis , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Enfermedades Renales , Mieloma Múltiple , Amiloidosis/patología , Humanos , Cadenas Ligeras de Inmunoglobulina , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Enfermedades Renales/patología , Mieloma Múltiple/patología , ProteómicaRESUMEN
INTRODUCTION: Thyroid carcinoma is the most common endocrine neoplasm. Multimodal therapy including surgery, radioactive iodine (RAI) therapy, and indefinite suppression of thyroid-stimulating hormone has led to an 85% cure rate in differentiated thyroid tumors (DTT). Approximately 5-10% of patients will have recurrence or metastases that have the potential to become resistant to RAI treatment.1 10-year overall survival rates are reported to be 10% in these patients versus 56% in patients with RAI avid disease.2 Lenvatinib, a multi-tyrosine-kinase inhibitor (TKI), was shown to have a 65% overall response rate in addition to a significant improvement in progression-free survival (PFS), approved to treat RAI-resistant DTTs.3, 4. CASE REPORT: We are reporting a very rare case of late renal toxicity in a 68-year-old woman with a history of type 2 diabetes and metastatic RAI-resistant follicular thyroid carcinoma (Hurthle cell variant) who developed thrombotic microangiopathy 21 months after initiation of treatment. MANAGEMENT & OUTCOME: It was determined that LEN should be held, due to worsening renal function secondary to TKI-induced kidney injury. Although the patient's renal function eventually improved and returned to her baseline after discontinuation of LEN, there was marked disease progression after drug cessation. DISCUSSION: Renal toxicity is a rare adverse event (AE) that tends to occur typically within three weeks of initiation of treatment. The utilization of TKIs can lead to glomerulosclerosis, and careful considerations and precautions should be taken by clinicians who intend to initiate TKI therapy in patients with pre-existing diabetes to prevent renal toxicity.
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Adenocarcinoma , Antineoplásicos , Diabetes Mellitus Tipo 2 , Quinolinas , Neoplasias de la Tiroides , Humanos , Femenino , Anciano , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/radioterapia , Radioisótopos de Yodo/efectos adversos , Diabetes Mellitus Tipo 2/inducido químicamente , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Compuestos de Fenilurea/efectos adversos , Quinolinas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/efectos adversosRESUMEN
Introduction: There are limited reports on kidney biopsy findings in patients with mantle cell lymphoma (MCL). Methods: We initiated a multi-institutional, retrospective review of kidney biopsy findings in patients with active and treated MCL. Results: A total of 30 patients with MCL and kidney biopsies were identified, with a median age of 67 (range 48-87) years, 73% of whom were men. A total of 20 patients had active MCL at the time of biopsy, of whom 14 (70%) presented with acute kidney injury (AKI), proteinuria and/or hematuria, and biopsy findings potentially attributable to lymphoma. Of the 14, 11 had immune complex (IC) or complement-mediated (C3) disease including proliferative glomerulonephritis (GN) with monotypic Ig deposits (PGNMID [2]), C3GN, (2), secondary membranous nephropathy (MN [3]), tubular basement membrane (TBM) deposits (2), and modest lupus-like GN (2). Lymphomatous infiltration was present in 8 of the 20 patients, 5 with coincident IC or C3 lesions. A total of 6 patients with available follow-up were treated for MCL, all with clinical remission of GN (2 PGNMID, 2 C3GN, and 2 MN). Conclusion: MCL is associated with diverse monoclonal and polyclonal glomerular and extra-glomerular IC and C3 disease. For patients with active MCL and kidney dysfunction requiring biopsy, 70% had findings due or potentially due to lymphoma, including 55% with IC or C3 disease and 40% had lymphomatous kidney infiltration. IC and C3GN in the setting of active MCL was responsive to lymphoma-directed therapy.
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C3 glomerulopathy (C3G) is a rare disease resulting from dysregulation of the alternative complement pathway, resulting in the deposition of complement component 3 (C3) in the kidney. It encompasses two major subgroups: dense deposit disease and C3 glomerulonephritis (C3GN). Although the alternative complement pathway is typically a very tightly controlled system, dysregulation can be a result of genetic mutations in the fluid phase or membrane-bound inhibitors or accelerators. In addition, de novo/acquired autoantibodies against any of the regulatory proteins can alter complement activation either by negating an inhibitor or activating an accelerator. Triggering events can be complex; however, the final pathway is characterized by the uncontrolled deposition of C3 in glomeruli and the formation of the membrane attack complex. Light microscopic findings can be quite heterogeneous with a membranoproliferative pattern most commonly encountered. Diagnostic confirmation of C3G is based on a characteristic pattern of glomerular immunofluorescence staining, with C3-dominant deposits that are at least 2 orders of intensity greater than staining for any immunoglobulin (Ig) or C1q. Electron microscopy is necessary for diagnosing DDD in particular, but can also help to distinguish C3GN from other glomerular disease mimickers.
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Background: For the better part of the past 6 decades, transmission electron microscopy (EM), together with routine light microscopy and immunofluorescence and/or immunohistochemistry (IHC), has been an essential component of the diagnostic workup of medical renal biopsies, particularly native renal biopsies, with increasing frequency in renal allograft biopsies as well. Studies performed prior to the year 2000 have indeed shown that a substantial fraction of renal biopsies cannot be accurately diagnosed without EM. Still, EM remains costly and labor-intensive, and with increasing pressure to reduce healthcare costs, some centers are de-emphasizing diagnostic EM. This trend has been coupled with advances in IHC and other methods in renal biopsy diagnosis over the past 2-3 decades. Summary: Nonetheless, it has been our experience that the diagnostic value of EM in the comprehensive evaluation of renal biopsies remains similar to what it was 20-30 years ago. In this review, we provide several key examples from our practice where EM was essential in making the correct renal biopsy diagnosis, ranging from relatively common glomerular lesions to rare diseases. Key Messages: EM remains an important component of the diagnostic evaluation of medical renal biopsies. Failure to perform EM in certain cases will result in an incorrect diagnosis, with possible clinical consequences. We strongly recommend that tissue for EM be taken and stored in an appropriate fixative and ultrastructural studies be performed for all native renal biopsies, as well as appropriate renal allograft biopsies as recommended by the Banff consortium.
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Background: Nephropathy in patients with thymic diseases such as thymoma and myasthenia gravis (MG) is rare and has been described mostly as isolated case reports. Here we evaluate a series of kidney biopsies from patients with thymoma and/or MG from a single institution in order to better define the spectrum and relative frequencies of thymic disease-associated nephropathies. Methods: We conducted a retrospective case series study of 32 462 native kidney biopsies from January 2005 through December 2019 at Cedars-Sinai Medical Center, Los Angeles, CA, USA. Results: Twenty-four biopsy specimens (0.07%) from patients with a history of thymoma and/or MG were identified. Two patients had repeat biopsies. The most common pathologic diagnosis that could be immunologically attributed to thymic disease was minimal change disease (MCD; 45%), followed by tubulointerstitial nephritis (TIN; 14%), immune complex (IC)-mediated glomerulonephritis (9%), membranous nephropathy (5%) and immunoglobulin A (IgA) nephropathy (5%). Interestingly, 50% of the MCD and 67% of TIN cases concomitantly showed mild IgG-dominant IC deposition in mesangial areas and/or in tubular basement membranes. In the two patients with repeat biopsies, mild mesangial IC deposition developed in the MCD patient but disappeared in the TIN patient with the second biopsy. Pathologic diagnoses unlikely related to the underlying thymic disease were diabetic glomerulosclerosis (9%), acute tubular necrosis (9%) and monoclonal Ig deposition disease (5%). Conclusions: Thymic disease is associated with a wide spectrum of kidney diseases affecting the glomerular and tubulointerstitial compartments, often with low-grade IC deposition. These findings suggest a role of immunologic dysregulation in the pathogenesis of thymic disease-associated nephropathy.
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Vascular endothelial growth factor (VEGF) inhibition can cause worsening hypertension, proteinuria, chronic kidney injury, and glomerular disease. Thrombotic microangiopathy (TMA) and other nephrotic disorders have been reported with systemic VEGF blockade. These same agents are given intravitreally for age-related macular degeneration (AMD) and diabetic retinopathy (DR), albeit at lower doses than those given for systemic indications. Systemic absorption of anti-VEGF agents when given intravitreally has been shown consistently along with evidence of significant intravascular VEGF suppression. While worsening hypertension has only been seen in some large-scale studies, case reports show worsening proteinuria and diverse glomerular diseases. These include TMA-associated lesions like focal and segmental glomerulosclerosis with collapsing features (cFSGS). In this paper, we report three cases of TMA likely associated with the use of intravitreal anti-VEGF therapy. These patients developed the signature lesion of VEGF blockade in a 6 to 11 month time frame after starting intravitreal VEGF inhibitors. The literature is reviewed showing similar cases. Intravitreal VEGF blockade may cause these adverse events in a hitherto unidentified subgroup of patients. Well-controlled prospective observational trials are needed to determine the event rate and identify which subgroups of patients are at increased risk. A registry for patients who develop worsening hypertension, proteinuria exacerbation, and glomerular diseases from intravitreal VEGF blockade is proposed.
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C3 dominant immunofluorescence staining is present in a subset of patients with idiopathic immune complex membranoproliferative glomerulonephritis (iMPGN). It is increasingly recognized that iMPGN may be complement driven, as are cases of "typical" C3 glomerulopathy (C3G). In both iMPGN and C3G, a frequent membranoproliferative pattern of glomerular injury may indicate common pathogenic mechanisms via complement activation and endothelial cell damage. Dysregulation of the alternative complement pathway and mutations in certain regulatory factors are highly implicated in C3 glomerulopathy (which encompasses C3 glomerulonephritis, dense deposit disease, and cases of C3 dominant MPGN). We report three cases that demonstrate that an initial biopsy diagnosis of iMPGN does not exclude complement alterations similar to the ones observed in patients with a diagnosis of C3G. The first patient is a 39-year-old woman with iMPGN and C3 dominant staining, with persistently low C3 levels throughout her course. The second case is a 22-year-old woman with elevated anti-factor H antibodies and C3 dominant iMPGN findings on biopsy. The third case is a 25-year-old woman with C3 dominant iMPGN, dense deposit disease, and a crescentic glomerulonephritis on biopsy. We present the varied phenotypic variations of C3 dominant MPGN and review clinical course, complement profiles, genetic testing, treatment course, and peri-transplantation plans. Testing for complement involvement in iMPGN is important given emerging treatment options and transplant planning.
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JC virus-associated nephropathy is rare in kidney transplant recipients, and even rarer in recipients of other solid organ transplants. We present a case of JC virus-associated nephropathy in a heart-kidney transplant recipient, which to our knowledge is the first case reported in the literature. We discuss the findings on renal biopsy for JC virus nephropathy and our management approach to this rare complication.