Glomerular Disorders PDF

Glomerular disorders Lecture Number 7.2 Status Done Type Lecture 7.2 Glomerular Disorders Overview Glomerular disorders represent a heterogeneous group of diseases affecting the glomeruli bilaterally, disrupting normal renal filtration and causing significant...

Glomerular disorders Lecture Number 7.2 Status Done Type Lecture 7.2 Glomerular Disorders Overview Glomerular disorders represent a heterogeneous group of diseases affecting the glomeruli bilaterally, disrupting normal renal filtration and causing significant clinical manifestations such as hematuria and proteinuria. These disorders are primarily classified by the extent of glomerular involvement, underlying pathogenic mechanisms, and histological changes. Most glomerular disorders involve immune-mediated damage, with various immunologic and non-immunologic mechanisms leading to the structural and functional alteration of the glomerular filtration barrier. Understanding these disorders is essential for diagnosing nephrotic and nephritic syndromes and managing associated systemic implications. Learning Objectives Objective 1: Describe the structural patterns and classifications of glomerular injury. Objective 2: Differentiate between focal, diffuse, segmental, and global patterns of glomerular involvement. Objective 3: Identify and explain the immunologic and pathogenic mechanisms underlying primary and secondary glomerular disorders. Objective 4: Distinguish between proliferative and non-proliferative glomerular disorders and relate them to nephrotic and nephritic syndromes. Objective 5: Explain the mechanisms of proteinuria and hematuria in glomerular diseases. Objective 6: Outline the indications, procedures, and interpretation of diagnostic tools, including kidney biopsy, urinalysis, and serology. Key Concepts and Definitions Glomerular Disorders: Diseases that bilaterally affect renal glomeruli, impairing their filtration function. Classification by Extent of Involvement: Focal: 50% of glomeruli are affected, indicating more extensive renal involvement. Segmental: Damage is restricted to a part of the glomerulus. Global: The entire glomerular tuft is involved. Classification by Pathogenesis: Primary Glomerular Disorders: Disorders originating within the kidney, frequently idiopathic, where the primary pathology is intrinsic to the glomerulus. Secondary Glomerular Disorders: Result from systemic diseases that impact the kidneys, such as autoimmune disorders, infections, or metabolic conditions. Classification by Histology: Proliferative Disorders: Increased cellularity within the glomerulus, often due to mesangial or endocapillary proliferation, common in nephritic syndromes. Non-Proliferative Disorders: Absence of increased cellularity, typically featuring changes in the GBM and podocytes, associated with nephrotic syndromes. Clinical Applications Case Study: A 45-year-old patient presents with significant edema and marked proteinuria (>3.5 g/day). A kidney biopsy reveals non-proliferative glomerular changes consistent with nephrotic syndrome.  Diagnostic Approach: Kidney Biopsy: Essential for definitive diagnosis, especially in distinguishing proliferative from non-proliferative disorders and assessing histological changes. The biopsy is the gold standard for diagnosing glomerular disorders but may not be required in cases like minimal change disease in children. Urinalysis: Assesses proteinuria, hematuria, and red blood cell casts to differentiate nephrotic from nephritic presentations. Serology: Tests for systemic causes, such as autoimmune markers in systemic lupus erythematosus (SLE), are helpful in diagnosing secondary glomerular disorders. Treatment Options: Immunosuppressants: Effective for immune-mediated glomerular disorders, particularly in nephritic syndromes with inflammatory or proliferative pathology. Steroids: First-line therapy for minimal change disease due to its high steroid sensitivity. ACE Inhibitors/ARBs: Commonly used to reduce proteinuria and protect renal function in chronic glomerular disease. Diuretics and Antihypertensives: Used to manage edema and hypertension commonly associated with glomerular diseases. Complications and Management: Proliferative Disorders: Can progress to chronic glomerulosclerosis due to ongoing inflammation and scarring. Non-Proliferative Disorders: Prolonged protein loss leads to hypoalbuminemia and potential thrombotic complications due to hypercoagulability in nephrotic syndrome. Pathophysiology Normal Glomerular Structure: Glomerulus Components: Formed by a capillary network lined by fenestrated endothelial cells, surrounded by the GBM, and enveloped by podocytes. Filtration Barrier: Includes the fenestrated endothelium, negatively charged GBM, podocytes, and slit diaphragm, crucial for size and charge-selective filtration. Bowman’s Space: Collects ultrafiltrate for passage into the proximal convoluted tubule. Immunologic Mechanisms: Primary Immunologic Mechanisms: Antibodies against GBM components or in-situ immune complexes provoke inflammation. Humoral Immunity: Formation of immune complexes, either circulating or in-situ, leading to mesangial or subendothelial deposition. Cellular Immunity: Imbalance in lymphocyte response, which can stimulate localized inflammation and cell- mediated damage. Secondary Immunologic Mechanisms: Complement activation, cytokine release, and coagulation cascade promote inflammation, vascular damage, and glomerular injury. Mechanisms of Injury: Proteinuria: Disruption of the slit diaphragm or GBM charge allows albumin and other proteins to cross into the urine. Hematuria: Structural breaks in the glomerular capillary wall permit red blood cells to leak into Bowman’s space. Pharmacology Steroids (e.g., Prednisone): Primarily for minimal change disease and some immune-mediated disorders to reduce inflammation. Immunosuppressants (e.g., Cyclophosphamide, Rituximab): Target immune-mediated injury in proliferative glomerular diseases. ACE Inhibitors/ARBs: Used to manage proteinuria, especially in non-proliferative, nephrotic disorders by reducing intraglomerular pressure and protein loss. Diuretics (e.g., Furosemide): Manage edema associated with nephrotic syndrome. Differential Diagnosis  Nephrotic Syndrome: Key Features: Heavy proteinuria (>3.5 g/day), hypoalbuminemia, hyperlipidemia, and edema. Common Disorders: Minimal change disease, membranous nephropathy, focal segmental glomerulosclerosis (FSGS). Nephritic Syndrome: Key Features: Hematuria, mild-to-moderate proteinuria, hypertension, and often oliguria. Common Disorders: IgA nephropathy, post-infectious glomerulonephritis, lupus nephritis. Other Causes of Proteinuria: Diabetes mellitus, hypertension, and amyloidosis should be considered when immune- mediated findings are absent. Investigations Kidney Biopsy: The gold standard for diagnosing glomerular diseases, particularly for distinguishing proliferative from non-proliferative pathology. However, not necessary in cases of minimal change disease in children due to steroid responsiveness. Urinalysis: Differentiates nephrotic (heavy proteinuria) from nephritic (hematuria, RBC casts) presentations and is a first- line diagnostic tool. Serology: Systemic disease markers such as ANA for lupus or ANCA for vasculitis help confirm secondary glomerular disorders. Additional Testing: Imaging (e.g., ultrasound) may be used to evaluate kidney structure, and renal function tests assess disease progression. Key Diagrams and Visuals Summary and Key Takeaways Takeaway 1: Glomerular disorders are complex and classified based on extent, pathogenesis, and histology, directly influencing the clinical and diagnostic approach. Takeaway 2: Damage to the glomerular filtration barrier, whether through immune complexes or cellular injury, disrupts filtration, resulting in hematuria and proteinuria. Takeaway 3: Biopsy and urinalysis are essential for distinguishing nephrotic and nephritic presentations and guiding treatment, with kidney biopsy being definitive in most cases. Further Reading/References Reference 1: "Practical Renal Pathology" – Detailed examination of glomerular filtration barrier and mechanisms of proteinuria and hematuria. Reference 2: "Human Histology" by Stevens and Lowe – Comprehensive visualization of normal glomerular structure and histopathologic changes in disease. Questions/Clarifications Question 1: What additional diagnostic markers can help differentiate between primary and secondary glomerular disorders in ambiguous cases? Question 2: How does long-term management differ between patients with recurrent nephrotic syndrome and those with chronic nephritic conditions? Question 3: What molecular pathways contribute to mesangial proliferation, and how do they relate to therapeutic targets for proliferative glomerular diseases?