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Nature Reviews. Nephrology Mar 2019The C3 glomerulopathies are a group of rare kidney diseases characterized by complement dysregulation occurring in the fluid phase and in the glomerular... (Review)
Review
The C3 glomerulopathies are a group of rare kidney diseases characterized by complement dysregulation occurring in the fluid phase and in the glomerular microenvironment, which results in prominent complement C3 deposition in kidney biopsy samples. The two major subgroups of C3 glomerulopathy - dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) - have overlapping clinical and pathological features suggestive of a disease continuum. Dysregulation of the complement alternative pathway is fundamental to the manifestations of C3 glomerulopathy, although terminal pathway dysregulation is also common. Disease is driven by acquired factors in most patients - namely, autoantibodies that target the C3 or C5 convertases. These autoantibodies drive complement dysregulation by increasing the half-life of these vital but normally short-lived enzymes. Genetic variation in complement-related genes is a less frequent cause. No disease-specific treatments are available, although immunosuppressive agents and terminal complement pathway blockers are helpful in some patients. Unfortunately, no treatment is universally effective or curative. In aggregate, the limited data on renal transplantation point to a high risk of disease recurrence (both DDD and C3GN) in allograft recipients. Clinical trials are underway to test the efficacy of several first-generation drugs that target the alternative complement pathway.
Topics: Autoantibodies; Autoimmunity; Biopsy; Complement C3; Humans; Kidney Diseases; Kidney Glomerulus; Rare Diseases
PubMed: 30692664
DOI: 10.1038/s41581-018-0107-2 -
Kidney International Dec 2013C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty...
C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group.
Topics: Biomedical Research; Biopsy; Complement C3; Cooperative Behavior; Glomerulonephritis; Humans; International Cooperation; Kidney Glomerulus; Predictive Value of Tests; Prognosis
PubMed: 24172683
DOI: 10.1038/ki.2013.377 -
Revista Da Associacao Medica Brasileira... Jan 2020Acute kidney injury is a very common diagnosis, present in up to 60% of critical patients, and its third main cause is drug toxicity. Nephrotoxicity can be defined as... (Review)
Review
Acute kidney injury is a very common diagnosis, present in up to 60% of critical patients, and its third main cause is drug toxicity. Nephrotoxicity can be defined as any renal injury caused directly or indirectly by medications, with acute renal failure, tubulopathies, and glomerulopathies as common clinical presentations. Some examples of drugs commonly associated with the acute reduction of glomerular filtration rate are anti-inflammatories, antibiotics, such as vancomycin and aminoglycosides, and chemotherapeutic agents, such as cisplatin and methotrexate. Cases of tubulopathy are very common with amphotericin B, polymyxins, and tenofovir, and cases of glomerulopathies are common with VEGF inhibitors, bisphosphonates, and immunotherapy, and it is also common to have more than one clinical presentation related to a single agent. Early diagnosis is essential for the good evolution of the patient, with a reduction of renal exposure to the toxic agent, which requires knowing the risk factors and biomarkers. General measures such as correcting hydroelectrolytic disorders and hypovolemia, monitoring the serum level, avoiding combinations with the synergy of renal injury, and looking for similar options that are less toxic are the foundations for the treatment of complications that are still common and often preventable.
Topics: Acute Kidney Injury; Drug-Related Side Effects and Adverse Reactions; Humans; Nephrotic Syndrome; Risk Factors
PubMed: 31939540
DOI: 10.1590/1806-9282.66.S1.82 -
Clinical Science (London, England :... Apr 2022Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy,...
Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy, and diabetic nephropathy (DN). Moreover, albuminuria is an important feature of all chronic kidney diseases (CKDs). Podocytes play a key role in maintaining the permselectivity of the glomerular filtration barrier (GFB) and injury of the podocyte, leading to foot process (FP) effacement and podocyte loss, the unifying underlying mechanism of proteinuric glomerulopathies. The metabolic insult of hyperglycemia is of paramount importance in the pathogenesis of DN, while insults leading to podocyte damage are poorly defined in other proteinuric glomerulopathies. However, shared mechanisms of podocyte damage have been identified. Herein, we will review the role of haemodynamic and oxidative stress, inflammation, lipotoxicity, endocannabinoid (EC) hypertone, and both mitochondrial and autophagic dysfunction in the pathogenesis of the podocyte damage, focussing particularly on their role in the pathogenesis of DN. Gaining a better insight into the mechanisms of podocyte injury may provide novel targets for treatment. Moreover, novel strategies for boosting podocyte repair may open the way to podocyte regenerative medicine.
Topics: Albuminuria; Autophagy; Diabetes Mellitus; Diabetic Nephropathies; Glomerulosclerosis, Focal Segmental; Humans; Podocytes
PubMed: 35415751
DOI: 10.1042/CS20210625 -
Internal Medicine (Tokyo, Japan) Mar 2021Collagenofibrotic glomerulopathy or LMX1B-associated nephropathy is a rare disease in which type III collagen accumulates in the glomeruli. We herein report a...
Collagenofibrotic glomerulopathy or LMX1B-associated nephropathy is a rare disease in which type III collagen accumulates in the glomeruli. We herein report a 64-year-old Japanese woman with an elevated serum creatinine level and persistent proteinuria for 7 years. An electron microscopic study using tannic acid showed curved and frayed collagen fibers within mesangial and subendothelial regions compatible with type III collagen depositions. The distribution of type IV collagen α1-6 chains was normal. Since no pathogenic mutations were identified in the LMX1B gene, she was diagnosed with collagenofibrotic glomerulopathy and treated with angiotensin II receptor blocker and calcium antagonist to control her blood pressure.
Topics: Collagen Type III; Female; Glomerular Mesangium; Humans; Kidney Diseases; Kidney Glomerulus; Middle Aged; Proteinuria
PubMed: 33055489
DOI: 10.2169/internalmedicine.6090-20 -
Clinical Journal of the American... Nov 2019In 2012, the Systemic Lupus International Collaborating Clinics proposed that lupus nephritis, in the presence of positive ANA or anti-dsDNA antibody, is sufficient to...
BACKGROUND AND OBJECTIVES
In 2012, the Systemic Lupus International Collaborating Clinics proposed that lupus nephritis, in the presence of positive ANA or anti-dsDNA antibody, is sufficient to diagnose SLE. However, this "stand-alone" kidney biopsy criterion is problematic because the ISN/RPS classification does not specifically define lupus nephritis. We investigated the combination of pathologic features with optimal sensitivity and specificity for the diagnosis of lupus nephritis.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Three hundred consecutive biopsies with lupus nephritis and 560 contemporaneous biopsies with nonlupus glomerulopathies were compared. Lupus nephritis was diagnosed if there was a clinical diagnosis of SLE and kidney biopsy revealed findings compatible with lupus nephritis. The control group consisted of consecutives biopsies showing diverse glomerulopathies from patients without SLE, including IgA nephropathy, membranous glomerulopathy, pauci-immune glomerulonephritis, membranoproliferative glomerulonephritis (excluding C3 GN), and infection-related glomerulonephritis. Sensitivity and specificity of individual pathologic features and combinations of features were computed.
RESULTS
Five characteristic features of lupus nephritis were identified: "full-house" staining by immunofluorescence, intense C1q staining, extraglomerular deposits, combined subendothelial and subepithelial deposits, and endothelial tubuloreticular inclusions, each with sensitivity ranging from 0.68 to 0.80 and specificity from 0.8 to 0.96. The presence of at least two, three, or four of the five criteria had a sensitivity of 0.92, 0.8, and 0.66 for the diagnosis of lupus nephritis, and a specificity of 0.89, 0.95, and 0.98.
CONCLUSIONS
In conclusion, combinations of pathologic features can distinguish lupus nephritis from nonlupus glomerulopathies with high specificity and varying sensitivity. Even with stringent criteria, however, rare examples of nonlupus glomerulopathies may exhibit characteristic features of lupus nephritis.
Topics: Adolescent; Adult; Aged; Biopsy; Female; Humans; Kidney; Lupus Nephritis; Male; Middle Aged; Retrospective Studies; Sensitivity and Specificity; Young Adult
PubMed: 31653670
DOI: 10.2215/CJN.01570219 -
Modern Pathology : An Official Journal... Feb 2018In the renal allograft, transplant glomerulopathy represents a morphologic lesion and not a specific diagnosis. The hallmark pathologic feature is glomerular basement... (Review)
Review
In the renal allograft, transplant glomerulopathy represents a morphologic lesion and not a specific diagnosis. The hallmark pathologic feature is glomerular basement membrane reduplication by light microscopy or electron microscopy in the absence of immune complex deposits. Transplant glomerulopathy results from chronic, recurring endothelial cell injury that can be mediated by HLA alloantibodies (donor-specific antibodies), various autoantibodies, cell-mediated immune injury, thrombotic microangiopathy, or chronic hepatitis C. Clinically, transplant glomerulopathy may be silent, detectable on protocol biopsy, or present with overt manifestations, including up to nephrotic range proteinuria, hypertension, and declining glomerular filtration rate. In either case, transplant glomerulopathy is associated with reduced graft survival. This review details the morphologic features of transplant glomerulopathy found on light microscopy, immunofluorescence microscopy, and electron microscopy. The pathophysiology of the causes and risk factors are discussed. Clinical manifestations are emphasized and potential therapeutic modalities are examined.
Topics: Graft Rejection; Humans; Kidney; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation
PubMed: 29027535
DOI: 10.1038/modpathol.2017.123 -
Clinical Journal of the American... Nov 2021Membranoproliferative GN and C3 glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific etiologic... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVES
Membranoproliferative GN and C3 glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific etiologic data for pediatric membranoproliferative GN/C3 glomerulopathy are lacking, and outcome data are based on retrospective studies without etiologic data.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
A total of 80 prevalent pediatric patients with membranoproliferative GN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using a Cox proportional hazards model. Kidney and transplant graft survival was determined using the Kaplan-Meier method.
RESULTS
Central histology review determined 39 patients with C3 glomerulopathy, 31 with immune-complex membranoproliferative GN, and ten with immune-complex GN. Patients were aged 2-15 (median, 9; interquartile range, 7-11) years. Median complement C3 and C4 levels were 0.31 g/L and 0.14 g/L, respectively; acquired (anticomplement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% of patients, respectively, across all groups, including those with immune-complex GN. Median follow-up was 5.18 (interquartile range, 2.13-8.08) years. Eleven patients (14%) progressed to kidney failure, with nine transplants performed in eight patients, two of which failed due to recurrent disease. Presence of >50% crescents on the initial biopsy specimen was the sole variable associated with kidney failure in multivariable analysis (hazard ratio, 6.2; 95% confidence interval, 1.05 to 36.6; 0.05). Three distinct C3 glomerulopathy prognostic groups were identified according to presenting eGFR and >50% crescents on the initial biopsy specimen.
CONCLUSIONS
Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric patients with membranoproliferative GN/C3 glomerulopathy and immune-complex GN. Presenting eGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquired abnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure.
Topics: Adolescent; Autoantibodies; Child; Child, Preschool; Complement C3; Complement C3b; Complement C4; Complement Factor B; Complement Factor H; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; Glomerulonephritis, Membranoproliferative; Graft Survival; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Male; Phenotype; Prognosis; Proportional Hazards Models; Prospective Studies; Recurrence; Registries; Risk Factors
PubMed: 34551983
DOI: 10.2215/CJN.00320121 -
Frontiers in Immunology 2022The specific B-cell depleting anti-CD20 monoclonal antibody rituximab (RTX) is effective in terms of the treatment of various immune-mediated glomerulopathies. The... (Review)
Review
The specific B-cell depleting anti-CD20 monoclonal antibody rituximab (RTX) is effective in terms of the treatment of various immune-mediated glomerulopathies. The administration of RTX has been shown to be reliable and highly effective particularly in patients with ANCA-associated vasculitis, which is manifested predominantly with non-nephrotic proteinuria. Stable long-term B-cell depletion is usually readily attained in such patients using standard dosing regimens. However, in patients with nephrotic syndrome and non-selective proteinuria, the RTX pharmacokinetics is altered profoundly and RTX does not maintain high enough levels for a sufficiently long period, which may render RTX treatment ineffective. Since complement-derived cytotoxicity is one of the important modes of action of RTX, hypocomplementemia, frequently associated with systemic lupus erythematodes, may act to hamper the efficacy of RTX in the treatment of patients with lupus nephritis. This review provides a description of RTX pharmacokinetics and pharmacodynamics in several selected glomerulopathies, as well as the impact of proteinuria, anti-drug antibodies and other clinical variables on the clearance and volume of distribution of RTX. The impact of plasmapheresis and peritoneal dialysis on the clearance of RTX is also discussed in the paper. A review is provided of the potential association between pharmacokinetic and pharmacodynamic alterations in various kidney-affecting glomerular diseases, the sustainability of B-cell depletion and the clinical efficacy of RTX, with proposals for potential dosing implications. The role of therapeutic drug monitoring in treatment tailoring is also discussed, and various previously tested RTX dosing schedules are compared in terms of their clinical and laboratory treatment responses. Since alternative anti-CD20 molecules may prove effective in RTX unresponsive patients, their pharmacokinetics, pharmacodynamics and current role in the treatment of glomerulopathies are also mentioned.
Topics: Humans; Rituximab; Antigens, CD20; Kidney Diseases; Proteinuria; Antibodies, Monoclonal
PubMed: 36420256
DOI: 10.3389/fimmu.2022.1024068 -
Clinical Kidney Journal Oct 2013Fibronectin glomerulopathy occurs between the second and fifth decades of life in most patients, and it is known to be slowly progressive with mild proteinuria leading...
Fibronectin glomerulopathy occurs between the second and fifth decades of life in most patients, and it is known to be slowly progressive with mild proteinuria leading to kidney failure. The case of a 78-year-old woman with a rapid course of nephrotic syndrome due to fibronectin glomerulopathy is reported. She had proteinuria that rapidly increased to 6.8 g/day in a month and microscopic haematuria. A renal biopsy specimen showed lobular glomerulopathy and membranoproliferative glomerulonephritis-like lesions on light microscopy. There was scanty staining for immunoglobulins and complement. Electron microscopy revealed granular deposits with fibril formation. Immunohistochemistry of the fibronectin showed intense staining in the mesangium and peripheral loop. Therefore, this case was diagnosed as fibronectin glomerulopathy. The kidney function was rapidly decreasing, necessitating haemodialysis 2 months after renal biopsy. It is important to consider fibronectin glomerulopathy in the differential diagnosis of nephrotic syndrome in older people.
PubMed: 26064516
DOI: 10.1093/ckj/sft097