Primary Glomerular Diseases: Part 2 - Nephrology PDF

Primary Glomerular Diseases Part 2 Axel Baez Torres, M.D.  Objectives Know the most common clinical disorders associated to the Nephrotic Syndrome Know the major causes of the Nephrotic Syndrome in children and adults Describe the etiology, mechanisms of injury, c...

Primary Glomerular Diseases Part 2 Axel Baez Torres, M.D.  Objectives Know the most common clinical disorders associated to the Nephrotic Syndrome Know the major causes of the Nephrotic Syndrome in children and adults Describe the etiology, mechanisms of injury, clinical course and prognosis of membranous nephropathy Describe the pathology of membranous nephropathy in terms of light microscopy, immunofluorescence and electron microscopy  Objectives Describe the etiology, mechanisms of injury, clinical course and prognosis of minimal change disease Describe the pathology of minimal change disease in terms of light microscopy and electron microscopy Describe the etiology, mechanism of injury, clinical course and prognosis of focal segmental glomerulosclerosis  Objectives Describe pathology of focal segmental glomerulosclerosis in terms of light microscopy and electron microscopy Describe the etiology, mechanisms of injury, clinical course and prognosis of membranoproliferative glomerulonephritis Describe the pathology of membranoproliferative glomerulonephritis in terms of light microscopy, immunofluorescence and electron microscopy  Objectives Describe the etiology, mechanisms of injury, clinical course and prognosis of IgA nephropathy Describe the pathology of IgA nephropathy in terms of light microscopy, immunofluorescence and electron microscopy Define clinical features of chronic glomerulonephritis List the most common glomerular disease leading to chronic glomerular nephritis  Objectives Describe the gross morphology of kidneys involved by chronic glomerulonephritis Describe the light microscopy features of kidneys involved by chronic glomerulonephritis Describe the clinical course and prognosis of patients with chronic glomerulonephritis Define acute tubular necrosis  Nephrotic Syndrome Glomerular syndrome characterized by heavy proteinuria (over 3.5 g of protein / 24 hours), hypoalbuminemia, severe edema, hyperlipidemia and lipiduria.  Causes of Nephrotic Primary Glomerular DiseaseSyndrome C A Membranous glomerulopathy 5% 30% Minimal change disease 65% 10% Focal segmental glomerulosclerosis 10% 35% Membranoproliferative glomerulonephritides 10% 10% Other proliferative glomerulonephritis (focal,"pure 10% 15% mesangial," IgA nephropathy)  Causes of Nephrotic Systemic Diseases Syndrome Diabetes mellitus Amyloidosis Systemic lupus erythematosus Drugs (nonsteroidal anti-inflammatory, penicillamine , "street heroin") Infections (malaria, syphilis, hepatitis B and C, acquired immunodeficiency syndrome) Malignant disease (carcinoma, lymphoma) Miscellaneous (bee-sting allergy, hereditary nephritis) Membranous Nephropathy Clinical Features – Common cause of nephrotic syndrome in adults due to primary glomerular disease – 80% - 90% of cases are idiopathic but the nephropathy may also occur in association with a number of disorders or exposure to antigenic substances: Systemic lupus Erythematosus Malignant neoplasms Exposure to gold and mercury Hepatitis B Membranous Nephropathy Etiology/Pathogenesis – Most “idiopathic” cases are caused by autoantibodies against the phospholipase A2 receptor (PLA2R), which is expressed on the podocyte. Then, the subepithelial deposits characteristic of the disease are thought to arise from in-situ immune complex formation. – Infectious agents, parasitic drugs and other planted antigens are those causative of the “secondary” form. Membranous Nephropathy Light Microscopy – The glomeruli may appear normal is the deposits are small (early disease). – Capillary walls are thickened, with sub-epithelial spikes on silver stain. Membranous Nephropathy Immunofluorescence Microscopy – Bright granular staining of the capillary loops with lgG and C3 Membranous Nephropathy Electron Microscopy – Subepithelial electron dense deposits with intervening basement membrane spikes – Stage of disease correlates with incorporation of deposits into the glomerular basement membrane Membranous Nephropathy Clinical Features – Treatment: Does not respond to steroid therapy. – Prognosis: Indolent clinical course in the majority of patients. Approximately 30-40% of patients eventually develop renal insufficiency.About10% die or progress to chronic renal failure within 10 years  Minimal Change Disease Clinical Features – The most common cause of the nephrotic syndrome in children – The disease is thought to be caused by a disorder of T lymphocytes, possibly production by T cells of a cytokine that increases glomerular permeability  Minimal Change Disease Clinical Features – Characterized by mild periorbital edema prior to the rapid onset of the nephrotic syndrome – Proteinuria is “selective” or composed primarily of albumin – Hematuria is rare – Hypertension is unusual  Minimal Change Disease Light Microscopy – The glomeruli, tubules and interstitium appears normal  Minimal Change Disease Immunofluorescence Microscopy – Usually negative  Minimal Change Disease Electron Microscopy – Diffuse effacement of the epithelial cell (podocyte) foot processes  Minimal Change Disease Prognosis – Over 90% of patients achieve complete remission with corticosteroid therapy – Intermittent relapses present frequently after withdrawal of steroids  Focal Segmental Glomerulsclerosis Clinical Features – Most common cause of Nephrotic Syndrome in adults due to primary glomerular disease.  Focal Segmental Glomerulsclerosis Clinical Features – The glomerulopathy may be primary (idiopathic) or secondary to a number of etiologic agents including: Unilateral renal agenesis Renal ablation Sickle cell disease Reflux nephropathy HIV infection  Focal Segmental Glomerulsclerosis Pathogenesis – Thought to be secondary to injury to, or dysfunction of podocytes; particularly related to conditions characterized by functional overwork over nephrons inducing glomerular hypertrophy. – Primary FSGS is thought to result from an undefined circulating factor or factors, which mediate abnormal glomerular permeability and ultimately sclerosis  Focal Segmental Glomerulsclerosis Pathogenesis – Some cases have a genetic basis involving mutations of genes whose protein products are components of the slit diaphragm  Focal Segmental Glomerulsclerosis Familial forms of FSGS – Congenital nephrotic syndrome of Finnish type: Autosomal recessive inheritance. Mutated NPHS1 gene produces an abnormal nephrin protein, a key component of the glomerular slit diaphragm – Corticosteroid-resistant nephrotic syndrome: Autosomal recessive inheritance. Mutated NPHS2 gene produces an abnormal podocin protein  Focal Segmental Glomerulsclerosis Familial forms of FSGS – Familial FSGS: Autosomal dominant inheritance. Mutations in Alpha-actinin 4 and Transient receptor potential cation channel- 6  Focal Segmental Glomerulsclerosis Light Microscopy – Focal (including some glomeruli) and segmental (involving part of a single glomerulus) sclerosis of the glomeruli with capillary loop collapse, hyaline and lipid deposition and often adhesion to Bowman’s capsule  Focal Segmental Glomerulsclerosis Immunofluorescence Microscopy – May show nonspecific entrapment of IgM or C3 in areas of sclerosis or may be negative  Focal Segmental Glomerulsclerosis Electron Microscopy – Effacement of podyte foot processes – Podocyte denudation may be present focally as an early lesion  Focal Segmental Glomerulsclerosis Prognosis – Not all patients improve with corticosteroid therapy – Most persons shows persistent proteinuria and progressive decline in renal function – Many patients progress to end- stage renal disease after 5 to 20 years – FSG recurs in half of transplanted kidneys  Membranoproliferative Glomerulonephritis Clinical Features – Chronic progressive glomerulonephritis most frequent in older children and young adults – Three types have been described, type I is the most common form – Patients may present with nephrotic syndrome, non- nephrotic proteinuria or the acute nephritic syndrome  Membranoproliferative Glomerulonephritis Clinical Features – Type I is most commonly idiopathic but may be associated with other systemic disorders such as subacute bacterial endocarditis,infected ventriculo- atrial shunts, hepatitis C virus infection and malignancy – Type II is thought to be an autoimmune disorder  Membranoproliferative Glomerulonephritis Pathogenesis – Type I is caused by deposition of immune complexes – Type II is caused be deposition of complement. The etiology is proposed to be prolonged C3 convertase activity induced by a circulating IgG autoantibody (“C3 nephritic factor”)  Membranoproliferative Glomerulonephritis Pathology – Type I and Type II MPGN are characterized by glomerular hypercellularity and capillary wall thickening – Type I MPGN electron microscopy shows subendothelial and mesangial deposits that contain C3, IgG and IgM by IF. – Type II MPGN electron microscopy show intramembranous deposits containing C3 (dense deposit disease). Deposits of immunoglobulins are not detected by IF.  Membranoproliferative Glomerulonephritis Prognosis – Type I is usually a persistent but slowly progressive disease. Half of patients reach end-stage renal disease after 10 years – Type II have a worst prognosis – Recurrence of MPGN after renal transplantation is frequent  IgA Nephropathy (Berger Disease) Clinical Features – Most common form of primary glomerulonephritis in the world – Geographic variability – May be related to a genetic or acquired abnormality of immune regulation leading to increased mucosal IgA synthesis in response to respiratory or gastrointestinal exposure to environmental agents  IgA Nephropathy (Berger Disease) Clinical Features – Occurs with increased frequency in patients with celiac disease, dermatitis herpetiformis and liver disease  IgA Nephropathy (Berger Disease) Clinical Features – Patients usually present with one of three syndromes: Macroscopic hematuria concurrent with an upper respiratory infection Asymptomatic hematuria and variable proteinuria Henoch-Schonlein purpura is the systemic form of disease and occurs more frequently in children  IgA Nephropathy (Berger Disease) Pathology – The light microscopy is variable – Immunofluorescence microscopy shows mesangial deposits of IgA  IgA Nephropathy (Berger Disease) Prognosis – Disease most often tends to be mild,but recurrent. About 25-50% of patients develop chronic renal failure within 20 years. Older patients tend to have a worst prognosis. Chronic Glomerulonephritis Clinical Features – End-stage pool of glomerular diseases fed by a number of different glomerulonephritides – A variable percentage of cases arise with no antecedent history of any of the well recognized forms of acute glomerulonephritis Chronic Glomerulonephritis Clinical Features – Disease is manifested by chronic renal failure and related uremic complications such as pericarditis, secondary hyperparathyroidism, anemia of chronic disease, etc. Chronic Glomerulonephritis Gross Morphology – Symmetrically contracted kidneys – Diffusely granular cortical surfaces – Thin cortex – Increased peripelvic fat Chronic Glomerulonephritis Microscopy – Glomeruli may still show evidence of primary disease or may show hyaline obliteration – Arterial/arteriolar sclerosis – Tubular atrophy – Interstitial fibrosis and chronic inflammation Chronic Glomerulonephritis Prognosis – Relentlessly progressive disease – If patients are not maintained with continued dialysis or if they do not received a renal transplant, the outcome is invariably death