Glomerulonephritis pathophysiologies for pharmacy

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1. Glomerulonephritis 1

2. Normal glomerular anatomy and function 2

3. Glomerulonephritis _ Inflammation of the glomerular capillaries Epidemiology and Etiology The third most common cause of end-stage renal disease (ESRD)_15% of all the living ESRD patients. 3

4. PATHOPHYSIOLOGY The glomerular capillary wall is particularly susceptible to immune-mediated injury either humoral and/or cellular immunologic Source of antigens may be from Glomerular epithelial or mesangial cells shed or epitopes Bacteria, fungi, and viruses can directly infect the kidney producing their own antigens. Autoimmune diseases like lupus nephritis. 4

5. Antigens and antibodies tend to localize in the glomerulus, probably because of its high blood flow and capillary hydrostatic pressure. Parenchymal damage can be induced as a result of humoral- and cell- mediated immune reactions. Antibodies and sensitized T lymphocytes are the primary mediators of glomerular injury. 5

6. Complexes of antigens and antibodies may be formed in the circulation and then passively entrapped in the glomerular capillary or mesangium . Impaired removal facilitates the growth of the complex and thus increases the likelihood of glomerular damage. Acute forms of glomerular injury frequently lead to chronic and persistent renal dysfunction , even though the original immune factors that induced the initial glomerular injury have resolved. 6

7. Variety of factors may participate in the progression of renal injury Systemic and glomerular hypertension High dietary protein intake Proteinuria Glomerular hypertrophy Hyperlipidemia Activation of the coagulation system, Abnormalities of calcium and phosphorus balance and Tubulointerstitial injury. 7

8. The glomerular lesion may be Diffuse (involving all glomeruli ), Focal (involving some but not all glomeruli ), or segmental, also known as local (involving part of the individual glomerulus). The pathologic manifestations may also be: Proliferative (overgrowth of epithelium,endothelium,or mesangium), Membranous (thickening of GBM), and/or Sclerotic. 8

9. Clinical Presentation Signs and symptoms are often categorized into one of two broad classifications: Nephritic syndrome __ reflects glomerular inflammation Syndromes are hematuria is typical in nephritic syndrome Pus- common cellular and granular casts in the urine- also common. Variable proteinuria 9

10. Nephrotic syndrome __ reflects non-inflammatory injury to the glomerular structures and results in. It is characterized by proteinuria greater than 3.5 g/day per 1.73 m2, hypoproteinemia , edema , and Hyperlipidemia hypercoagulable state few cells or cellular casts in the urine 10

11. The nephrotic syndrome may be the result of Primary diseases of the glomerulus, or systemic diseases such as diabetes mellitus, lupus, amyloidosis , and preeclampsia. 11

12. General __ The patients are generally not in acute distress Symptoms _ The patients may not experience any major symptoms. Nephritic Signs Hematuria __ highly indicative of glomerulonephritis or vasculitis Hypertension and edema as renal function declines Nephrotic Signs Edema Weight gain Fatigue 12

13. Laboratory Tests Proteinuria up to 3 g/day Pus, cellular and granular casts in urine is common Hypoproteinemia Hypercoagulable state for some patients Proteinuria, >3.5 g/day/1.73 m2 Hyperlipidemia Lipiduria 13

14. Hematuria occurs when red blood cells leak through the openings of the GBM. The presence of red cell casts is highly indicative of glomerulonephritis or vasculitis The presence of proteinuria indicates a defect of the size-and/or charge-selective barriers within the GBM. Normal urinary protein excretion is between 40 and 80 mg/day, with a maximum of 150 mg. Fewer than 20 mg of the excreted proteins are albumin. Most of the albumin that enters the glomerular filtrate is either reabsorbed or catabolized by the tubular epithelium 14

15. Diagnostic Considerations 15

16. Diagnostic Considerations 16

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18. Treatment General Approach to Treatment Diagnosis of underlying etiology for glomerular disease~__ because it affects the course and prognosis Specific treatment approaches for different glomerulonephritides 18

19. Non-pharmacologic Therapy Patients with Nephrotic syndrome, Dietary measures involve restriction of sodium intake to 50 to 100 mEq /day (50 to 100 mmol /day), protein intake of 0.8 to 1 g/day, a low-lipid diet of less than 200 mg cholesterol. Stop smoking 19

20. Pharmacologic Therapy Immunosuppressive agents, Used alone or in combination, to alter the immuno processes that are responsible for the glomerulonephritides . Drugs used are: Corticosteroids Cytotoxic agents, such as cyclophosphamide , chlorambucil , or azathioprine Mycophenolate mofetil 20

21. Diuretics Frequently required due to: severe salt restriction is difficult to achieve and prolonged bed rest can predispose nephrotic patients to thromboembolism Large doses of the loop diuretic, such as 160 to 480 mg, of furosemide for moderate edema due to: presence of large amounts of protein in the urine promotes drug binding reduced sodium delivery to the distal tubule 21

22. Antihypertensive Agents Important in reducing both the progression of renal disease and the risk for cardiovascular disease. ACEIs and ARBs delay the loss of renal function for patients with diabetic and nondiabetic (primarily glomerulonephritis) renal diseases. Nondihydropyridine CCBs reduce proteinuria and preserve renal function and could be used as an additional agent. Dihydropyridine CCBs are effective in lowering blood pressure, but without the benefit of proteinuria reduction. 22

23. Antiproteinuria Agents Protienuria is independent risk factor for renal function decline and cardiovascular disease Reducing proteinuria can retard renal function loss and delay the progression to ESRD. These are: Dietary protein restriction 23

24. ACEIs and ARBs The anti- proteinuric effect of ACEIs is associated with: Reduction in intraglomerular pressure__ fall in filtration fraction of peotiens . Direct effects on podocytes__ resulting in reduction of proteinuria and glomerular scarring reduce the effect of angiotensin II on renal cell proliferation, thereby reducing sclerosis 24

25. The combined use of an ACEI and an ARB reduces the rate of renal function decline more than either treatment alone.????????????? conrtoversy . maximizes blockade of the RAAS by counteracting the effects of Ang - II produced by non-ACE pathways. ARB should therefore be added to the regimen for those patients who do not attain full and persistent remission of proteinuria with an ACEI alone. 25

26. Non-steroidal Anti-inflammatory Agents Indomethacin and meclofenamate are the two most evaluated NSAIDs Reduce proteinuria__ by prostaglandin E2 inhibition__ resulting in a reduction of intraglomerular pressure__ decrease in GFR__ restoration of the barrier size selectivity of the GBM. Adherence to a low-sodium diet or concurrent use of a diuretic is needed to maximize the antiproteinuric effect 26

27. Statins Important to treat patients with: Persistent nephrotic syndrome and sustained dyslipidemia . concurrent atherosclerotic cardiovascular disease, or with additional risk factors for atherosclerosis, such as smoking and hypertension. The combined use of an ACEI with a statin may offer additional benefits in controlling nephrotic hyperlipidemia 27

28. Anticoagulants Documented thromboembolic episodes should be anti-coagulated with warfarin until remission of nephrotic syndrome. prophylactic anticoagulation is beneficial for patients with membranous nephropathy. those at high risk nephrotic syndrome and a serum albumin concentration <2 to 2.5 g/ dL [<20 to 25 g/L]). prolonged bed rest. Receiving high-dose IV steroid therapy, postsurgical patients 28

29. Monitoring Parameters to Assess Response to Glomerulonephritis Treatment. 29

30. Minimal-Change Nephropathy Epidemiology and Etiology 70–90% of nephrotic syndrome in childhood but only 10–15% of nephrotic syndrome in adults Usually presents as a primary renal disease but can be associated with several other conditions, including Hodgkin’s disease, allergies, or use of NSAIDs; significant interstitial nephritis often accompanies cases associated with non-steroidal drug use 30

31. Pathophysiology Characterized by the absence of definitive pathologic changes observed under light and immunofluorescence microscopy . The pathophysiology of this lesion is uncertain. Most agree there is a circulating cytokine, perhaps related to a T cell response that alters capillary charge and podocyte integrity 31

32. The activated lymphocytes are thought to secrete lymphokines that reduce the production of anions in the GBM__ increased to the permeability of the GBM to plasma The loss of anionic charges also results in fusion of the epithelial cell foot processes 32

33. Clinical Presentation Edema __ present initially with acute onset Nephrotic syndrome with massive proteinuria Hypoalbuminemia , and hyperlipidemia Less common clinical features include: hypertension (30% in children, 50% in adults), microscopic hematuria (20% in children, 33% in adults), atopy or allergic symptoms (40% in children, 30% in adults), and Decreased renal function (<5% in chil - dren , 30% in adults). 33

34. TREATMENT Pharmacologic Therapy Steroids Corticosteroids Reduce proteinuria in appro . 90% of the patients. Prednisone 60 mg/m2 per day initially for 4 to 6 weeks followed by 4 – 6weeks of 40 mg/m2 every other day. Proteinuria will disappear in 50% of patients after 1 week and in 90% of patients after 4 weeks of treatment. 34

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37. Cytotoxic Agents Are often considered for patients who are: Steroid resistant Steroid dependent__ require large doses of steroids to sustain remission. For paediatric patients who experience growth inhibition secondary to chronic use of steroids . Drugs include: Cyclophosphamide , chlorambucil , Azathioprine 37

38. Calcineurin Inhibitors__ cyclosporine Decreases lymphokine production by activated T lymphocytes__ by reversing the lymphokine -induced alterations in the anionic charge and permeability of the GBM to albumin. For patients with steroid-sensitive or steroid-dependent disease , cyclosporine induces remission in 80% to 85% of patients. Have steroid-sparing effects_ useful for steroid-dependent patient and significant adverse effects. 38

39. Mycophenolate Mofetil It is an immunosuppressant that can suppress T- and B-cell lymphocyte proliferation, B-lymphocyte antibody production, and expression of adhesion molecules. It is reported to have steroid-sparing effects and is useful in frequently relapsing, steroid-dependent and steroid-resistant patients, as well as in those who fail cytotoxic therapy. 39

40. Presentation Focal Segmental Glomerulosclerosis Membranous Nephropathy Membranoproliferative Glomerulonephritis Immunoglobulin A Nephropathy Lupus Nephritis Rapidly Progressive Glomerulonephritis Poststreptococcal Glomerulonephritis 40