glomerulonephritis givonce.pptx.........

Presentation of glomerulonephritis showing the aetiology, pathophysiology, risk factors and management. The presentation was prepared and presented by Moi University student together with their lecturer.

1. Glomerulonephritis Presenter: Givonce Brian Facilitator: Prof. Owino Ong’or

2. Introduction Glomerulonephritis (GN) presents as a constellation of findings that includes Hematuria Edema Hypertension (+/- proteinuria, +/- RF) group of disorders characterized by glomerular injury with or without inflammation hence glomerulopathy May progress to renal failure

3. Glomerulonephritis refers to a set of renal diseases in which an immunologic mechanism triggers inflammatory and proliferation of the glomerular tissue that can result in damage to the basement membrane, mesangium or capillary epithelium

4. GN is an immunologically mediated disorder with involvement of cellular immunity (T lymphocytes, macrophages/dendritic cells humoral immunity (antibodies, immune complexes, complement), inflammatory mediators (cytokines, chemokines , coagulation cascade). Mostly antigenic target is unknown but can be against infections, tumors and glomerular basement membrane

5. Primary GN may occur in genetically susceptible individuals following an environmental insult. The genetic susceptibility determined by major histocompatibilty complex (HLA) genes (e.g. HLA-A1, B8, DR2, DR3). The environmental factors may be drugs (e.g. hydralazine) chemicals (e.g. gold, silica, hydrocarbons) infectious agents

6. Pathological terms Focal : some but not all the glomeruli contain the lesion Diffuse (global): most of the glomeruli (> 75%) contain the lesion Segmental : only a part of the glomerulus is affected Proliferative : an increase in cell number due to hyperplasia of one or more of the resident glomerular cells with or without inflammation Membrane alterations : capillary wall thickening due to deposition of immune deposits or alterations in basement membrane Crescent formation : epithelial cell proliferation with mononuclear cell infiltration in Bowman's space

7. The glomerular Glomerulus contains three main cell types: endothelial cells lining the glomerular capillaries epithelial cells (podocytes) mesangial cells lie in the central region of the glomerulus - have similarities to vascular smooth muscle cells (e.g. contractility), but also some macrophage-like properties Filtration occurs across GBM, produced by fusion of the BMs of epithelial and endothelial cells. Glomerular capillary endothelial cells contain pores (fenestrae) which allow access of circulating molecules to the underlying GBM. On outer side of GBM, glomerular podocytes put out multiple long foot processes which interdigitate with those of adjacent epithelial cells As well as maintaining the filtration barrier, podocytes are involved in the regulation of filtration and of GBM turnover. properties.

8. Glomerular filtration barrier is composed of:- fenestrated capillary endothelium basement membrane intercalated podocyte foot processes The filtration barrier has a –ve ionic charge due to –vely charged molecules:- Proteoglycans e.g. heparan sulfate Glycoproteins e.g. sialic acid.

9. The glomerular filtrate: Cell free Contains all substances in plasma e.g. electrolytes, glucose, phosphate, urea, creatinine, peptides & LMW proteins, EXCEPT proteins of a MW of >/=68KDA e.g. albumin and globulins. Factors restricting filtration of plasma proteins: size ionic charge.

10. classification Based on clinical presentation Based on aetiology Based on histopathology

11. Based on clinical course Acute glomerulonephritis - sudden onset of hematuria with or without proteinuria , decreased GFR , and retention of Na and water, which usually results in HTN and edema Rapidly progressive glomerulonephritis - features of acute GN and by progressive loss of renal function over a comparatively short period of time (days, weeks, or months) Recurrent macroscopic/microscopic hematuria - transient episodes of macroscopic hematuria e.g. in IgA nephropathy Chronic glomerulonephritis - overt symptoms, and asymptomatic hematuria or proteinuria discovered on routine urinalysis. Late stage - present with hypertension, renal impairment, and proteinuria with or without hematuria.

12. Based on etiology Primary GN (disease process isolated to the kidney) Membranoproliferative glomerulonephritis Membranous glomerulopathy IgA nephropathy Idiopathic crescentic GN ( RPGN) Focal segmental glomerulonephritis Minimal change disease(lupoid nephrosis) Acute diffuse proliferative glomerulonephritis

13. Secondary GN (renal disease is a component of a systemic disorder) Post-streptococcal GN Non-streptococcal post-infectious GN, e.g. Staphylococcus , pneumococcus, Legionella , syphilis, mumps, varicella, hepatitis B and C, echovirus, EBV, toxoplasmosis, malaria, schistosomiasis, trichinosis Subacute Bacterial Endocarditis Henoch- Schönlein purpura SLE nephritis Granulomatosis with polyangiitis (formerly called Wegener’s granulomatosis) Microscopic polyangiitis

14. Spectrum of glomerulopathies Glomerulopathies presentation ranges from nephritic to nephrotic spectrum

15. Nephritic syndrome Nephritic syndrome is inflammation of the glomerular presenting with inflammation and bleeding Patients have limited proteinuria <3.5g/day together with oliguria, azotemia and bleeding The red blood cell cast in urine are dysmorphic Salt retention causes periorbital oedema and hypertension

16. Nephrotic syndromes Glomerular disorders with hallmark proteinuria > 3.5 g/day Patients presents with hypoalbuminemia, hypogammaglobinemia, hypercoagulable state and hyperlipidemia

17. POST-STREPTOCOCCAL GN Caused by prior infection with specific nephritogenic strains of group A beta-hemolytic streptococcus. Typically affects children under 10 years with streptococcal infection, Latent period of 1-3 weeks from onset of pharyngitis , 3- 6 weeks in skin infection. Bacterial endocarditis, visceral abscess, ventriculoperitoneal shunt infections can also lead to immune complex mediated disease Prognosis is generally favorable, especially in children, but in some cases, the long-term prognosis is not benign.

18. Epidemiology PSGN primarily occurs in developing countries 97% occur in developing countries, with annual incidence that ranges from 9.5 - 28.5 per 100,000 individuals In more developed and industrialized countries, the incidence has decreased over the past three decades (better health delivery and improved socioeconomic conditions) 5-15 years

19. Pathogenesis Caused by glomerular immune complex disease induced by specific nephritogenic strains of group A beta-hemolytic streptococcus (GAS). The resulting glomerular IC disease triggers complement activation and inflammation Following are proposed mxns for the immunologic glomerular injury induced by GAS infection: Deposition of circulating ICs with streptococcal antigenic components In situ IC formation resulting from deposition of strep Ags within the GBM and subsequent Ab binding In situ glomerular IC formation promoted by Abs to strep Ags that cross-react with glomerular components (molecular mimicry) Alteration of a normal renal Ag that elicits autoimmune reactivity

20. Pathology Light microscopy Diffuse proliferative GN with prominent endocapillary proliferation and numerous neutrophils Trichrome stain may show small subepithelial hump-shaped deposits. Crescent formation is uncommon and is ass. with a poor prognosis. Immunofluorescence microscopy Characteristic pattern of deposits of IgG and C3 distributed in a diffuse granular pattern within the mesangium, and glomerular capillary walls Electron microscopy Dome-shaped subepithelial and subendothelial electron-dense deposits that are referred to as humps - are immune complexes and correspond to the deposits of IgG and C3 found on IF

21. Clinical manifestations Varies from asx, microscopic hematuria to full-blown acute nephritic syndrome, characterized by red to brown urine, proteinuria (which can reach the nephrotic range), edema, hypertension, and an elevation in serum creatinine Antecedent history of a grp A beta-hemolytic streptococcal (GAS) skin or throat infection The latent period between GAS infection and PSGN is dependent upon the site of infection: between 1-3 weeks following GAS pharyngitis between 3-6 weeks following GAS skin infection

22. Most common presenting signs in children: Edema — Generalized edema - two-thirds of patients due to Na and water retention. In severe cases, fluid overload leads to respiratory distress due to pulmonary edema. Gross hematuria — Gross hematuria is present in about 30 – 50% of patients. Urine looks smoky, and tea or coca cola-colored. HTN —Present in 50 – 90% of patients and varies from mild to severe. Primarily caused by fluid retention. Subclinical cases of PSGN are primarily characterized by microscopic hematuria PSGN is associated with a variable decline in GFR that is detected by a rise in serum creatinine. Acute renal failure requiring dialysis is uncommon.

23. Lab findings Urinalysis:  Hematuria (some RBCs are typically dysmorphic) with or without red blood cell casts Varying degrees of proteinuria (Nephrotic range proteinuria is uncommon and occurs in about 5%) Often pyuria Complement:  In about 90% of patients, C3 and CH50 (total complement activity) are significantly depressed in the first 2weeks of disease course (if C3 doesn’t normalise – think MPGN) In comparison, C4 and C2 levels are usually normal or mildly decreased. The combination of a low C3 level and a normal or only slightly decreased C4 level indicates activation of the alternative pathway of complement Culture: 25% of patients will have either a positive throat or skin culture

24. Serology Elevated titers of Abs to extracellular streptococcal products is evidence of a recent GAS infection. The streptozyme test, which measures five different streptococcal antibodies, is positive in more than 95% of pts due to pharyngitis and about 80% of those with skin infections. It includes the following Abs: Anti-streptolysin (ASO) Anti-hyaluronidase (AHase) Anti-streptokinase (ASKase) Anti-nicotinamide-adenine dinucleotidase (anti-NAD) Anti-DNAse B antibodies After a pharyngeal infection, the ASO, anti-DNAse B, anti-NAD, and AHase titers are commonly elevated. In comparison, only the anti-DNAse B and AHase titers are typically increased after a skin infection .

25. Renal biopsy Not performed in most patients to confirm dx of PSGN, since clinical history is usually highly suggestive and resolution of PSGN typically begins within one week of presentation. Performed in patients in whom other glomerular disorders are being considered because they deviate from the natural course of the PSGN or they present late without a clear history of prior streptococcal infection. Persistently low C3 levels beyond six weeks are suggestive of a diagnosis of membranoproliferative GN Recurrent episodes of hematuria are suggestive of IgA nephropathy and are rare in PSGN. A progressive increase in serum creatinine is uncharacteristic of PSGN, but there are occasional patients who do not recover from the acute episode.

26. Differential diagnosis Membranoproliferative glomerulonephritis (MPGN) — Presentation of MPGN may be indistinguishable initially from PSGN. However, patients continue to have persistent nephritis and hypocomplementemia beyond 4-6 weeks and possibly a further elevation in serum creatinine. IgA nephropathy Shorter time between the antecedent illness and hematuria is (less than 5 versus more than 10 days in PSGN) Hx of prior episodes of gross hematuria since recurrence is rare in PSGN.

27. Secondary causes of GN: Lupus nephritis and HSP nephritis share similar features. However, extrarenal manifestations of the underlying systemic diseases and laboratory testing should differentiate them from PSGN. Measurement of serum complement may also be helpful. Hypocomplementemia is not characteristic of HSP and the hypocomplementemia that occurs in lupus nephritis is, ass. with reductions in both C3 and C4, whereas C4 levels are normal in PSGN Postinfectious GN due to other microbial agents: Acute nephritis due to viral and other bacterial agents has been reported Presentation is similar to PSGN except - no documentation of an antecedent GAS infection.

28. MANAGEMENT No specific therapy for PSGN. Management is supportive and focused on treating the clinical manifestations, particularly complications due to volume overload. General measures include sodium and water restriction and loop diuretics: IV furosemide  - given at initial dose of 1 mg/kg (maximum 40 mg). Infrequently, patients have hypertensive encephalopathy due to severe HTN - treated emergently to reduce their BP. Patients with PSGN have variable reductions in renal function, and some patients require dialysis during the acute episode. Patients with evidence of persistent group A streptococcal infection should be given a course of antibiotic therapy ( penicillins )

29. Course Resolution of the clinical manifestations of PSGN is generally quite rapid, A diuresis typically begins within one week Serum creatinine returns to the previous baseline by 3-4 weeks Urinary abnormalities disappear at differing rates. Hematuria usually resolves within 3-6 months Proteinuria also falls during recovery, but at a much slower rate ( upto 2 years)

30. Prognosis Most patients, particularly children, have an excellent outcome This is true even in patients who present with ARF and may have crescents on the initial renal biopsy However, the long-term prognosis of PSGN is not always benign Some patients, particularly adults, develop HTN, recurrent proteinuria (with a relatively normal urine sediment), and renal insufficiency as long as 10 - 40 years after the initial illness

31. IgA NEPHROPATHY IgA nephropathy is the most common lesion found to cause primary GN throughout most developed countries of the world There is a focal and segmental proliferative GN with mesangial deposits of polymeric IgA – typically IgA1 In some cases IgG, IgM and C3 may also be seen in the glomerular mesangium . Superimposed crescent formation is frequent, particularly following macroscopic hematuria due to URTI Several diseases may be associated with IgA deposits, including HSP, chronic liver disease, malignancies (especially carcinoma of bronchus), seronegative spondylarthritis, coeliac disease, mycosis fungoides and psoriasis

32. Clinical presentation Tends to occur in children and young males. Present with microscopic haematuria or recurrent macroscopic haematuria sometimes following a URTI or GI viral infection Proteinuria occurs and 5% can be nephrotic. Prognosis is usually good, especially in those with normal BP, normal renal function and absence of proteinuria at presentation. Surprisingly, recurrent macroscopic haematuria is a good prognostic sign, The risk of eventual development of ESRD is about 25% in those with proteinuria of >1 g per day, elevated serum creatinine, HTN, ACE gene polymorphism (DD isoform) and tubulointerstitial fibrosis on renal biopsy.

33. Management Patients with proteinuria over 1-3 g/day, mild glomerular changes only and preserved renal function should be treated with steroids . Steroids reduce proteinuria and stabilize renal function. In patients with progressive disease ( cretinine clearance < 70 mL/min), fish oil or prednisolone with cyclophosphamide for 3 months followed by maintenance with prednisolone and azathioprine may be tried. Tonsillectomy can reduce proteinuria and hematuria in those patients with recurrent tonsillitis. All patients, with or without HTN and proteinuria, should receive a combination of ACEI and ARB rather than each agent alone because reduction of proteinuria and preservation of renal function are better with combination therapy despite similar BP control.

34. RAPIDLY PROGRESSIVE GN (RPGN) Clinical syndrome manifested by features of glomerular disease in the urine and by progressive loss of renal function over a comparatively short period of time (days, weeks or months). Characterized morphologically by extensive crescent formation The 'crescent' is an aggregate of macrophages and epithelial cells in Bowman's space

35. Pathogenesis of crescent formation Appears to represent a nonspecific response to severe injury to the glomerular capillary wall Rents are induced in the glomerular capillary wall, resulting in the movement of plasma products, including fibrinogen, into Bowman's space with subsequent fibrin formation, influx of macrophages and T cells, and release of proinflammatory cytokines, such as IL-1 TNF-alpha Thus, crescents may be seen with any form of severe glomerular disease, including lupus nephritis and postinfectious GN

36. Classification Type 1: Anti-GBM  Refers to anti-GBM antibody disease Type 2: Immune complex  Nature of the immune deposits is not diagnostic of a specific disorder (which is rare) Type 3: Pauci-immune There is a necrotizing GN but few or no immune deposits by immunofluorescence or electron microscopy Majority of patients with renal-limited vasculitis are ANCA-positive Type 4: Double-antibody positive disease Has features of both types 1 and 3.

37. Clinical presentation Presenting complaints in RPGN may be similar to those in severe postinfectious GN - acute onset of macroscopic hematuria, decreased urine output, and edema. More commonly - insidious onset with initial sx - fatigue or edema Renal insufficiency is present at dx in almost all cases, with plasma creatinine concentration often exceeding 3 mg/dL (264 micromol/L). Systemic complaints, including extrarenal organ involvement, are common in patients with pauci-immune RPGN. Patients with anti-GBM antibody disease may also have pulmonary hemorrhage and hemoptysis due to Abs directed against the alveolar basement membranes.

38. Diagnosis urinalysis typically reveals dysmorphic hematuria, red cell and other casts, and a variable degree of proteinuria. the marked reduction in glomerular filtration rate usually limits the rate of protein filtration Renal biopsy Serologic tests ANCA, anti-GBM antibodies, complement component assays ANA

39. Treatment Untreated RPGN typically progresses to ESRD over a period of weeks to a few months. However, patients with fewer crescents may have a more protracted, not so rapidly progressive course Therapy of most patients with RPGN involves pulse methylprednisolone followed by daily oral prednisone, oral or IV cyclophosphamide and, in some settings, plasmapheresis. Early dx with renal biopsy and serologic testing and early initiation of appropriate therapy is essential to minimize the degree of irreversible renal injury.

40. Nephrotic syndromes Minimal change nephropathy Membranous Nephropathy Focal segmental glomerulosclerosis Hereditary Nephropathies

41. Albumin

42. Minimal change disease/lipoid nephrosis Primary / idiopathic Secondary due to:- Allergies Drugs e.g. NSAIDS, Rifampin, interferon alpha. Hodgkin's disease HIV DM Heroine use Iron dextran administration

43. Pathology 90% of NS in children <10yrs ~10% in adults Pathology is due to production cytokines that efface the processes of the podocytes on the glomerular wall LM – normal glomeruli or mild mesangial cell proliferation, EM - fusion of podocyte foot processes i.e. flattening, retraction and swelling (effacement) together with loss of –ve charge. Leading to selective proteinuria (loss of albumin but not immunoglobulin) as there is ↓d filtration barrier. IF - No evidence of IC deposition. The proximal tubular cells are laden with lipid and protein reflecting tubular reabsorption of lipoproteins passing through the diseased glomeruli thus the term lipoid nephrosis .

44. Focal Segmental Glomerulosclerosis (FSGS) Primary/Idiopathic – 10% in children and 35% in adults. Secondary (anything causing scarring of the kidney) Viruses e.g. HIV(collapsing variant), hep B, Hypertensive nephropathy Reflux nephropathy DM Renal dysgenesis (agenesis of 1 kidney). Radiation nephritis Sickle cell disease Cholesterol emboli

45. FSGS LM - presence (in some but not all -focal glomeruli) of segmental areas of mesangial collapse/ sclerosis. In sclerotic segments: collapse of the basement membranes increase in matrix segmental insudation of plasma proteins along the capillary wall (hyalinosis) EM - foot process fusion or -focal detachment of epithelial cells - denudation of underlying GBM. IF : No immune complex deposition

46. FGS Diffuse epithelial cell foot process fusion Occasional loss of the epithelial cells (arrows) Massive subendothelial hyaline deposits (Hy) under the GBM-insudation of plasma proteins, not the deposition of Igs 4. Narrowing of the capillary lumens

47. Membranous nephropathy 25-30 % (majority) of idiopathic NS in adults Peak-4 th -5 th decade, All races M:F 2-3:1, Male predominance at ESRD Usually idiopathic but may be associated with hepatitis B or C, solid tumors, SLE LM : BM thickening with little or no cellular proliferation or infiltration. EM - Thickening is caused by irregular Subepithelial dome and spike appearance on EM IF – demonstrates granular deposits of Igs and complement IgG & c3.

48. Summary… Normal glomerulus Membranous GN (MGN) Minimal chenge nephropathy (MCN) MCD: Fusion of pedics Memb . Nephropathy Subepithelial deposits FGS: Sclerotisation of the loops (here in perihilar region) 1 . 2 . 3 . 4 .

49. PATHOPHYSIOLOGY Proteinuria The filtration barrier (podocytes) impermeable to proteins the size of albumin(67kda) or larger. At physiological pH, most proteins negatively charged and BM also negatively charged, most proteins are retained Proteinuria: p erturbed negative electrostatic charge Change in architecture of: GBM or Podocytes and their slit diaphragms

50. Glomerular proteinuria can be (a)Selective proteinuria - If only intermediate-sized (< 100kDa) proteins: (albumin(67kda), transferrin(88kda)), leaks through the glomerulus (b)Non-selective proteinuria -When a range of different sized proteins leak through including larger proteins like IgG(150kda).

51. Proteinuria cont… increase in glomerular permeability influenced by glomerular filtration rate, the plasma concentration of albumin, and dietary protein intake Proteins lost ; Albumin , Peptide hormones, Clotting inhibitors eg anti-thrombin factor III ,Protein C and S, Hormone carrying proteins : Transferrin, cholecalciferol-binding protein , thyroxine-binding globulin

52. Edema Underfilling hypothesis: hypoalbuminemia results in ↓ intravascular oncotic pressure, leading to leakage of extracellular fluid from blood to the interstitium. Intravascular volume falls, thereby stimulating the RAAS axis, the sympathetic nervous system and release of vasopressin , and suppressing atrial natriuretic peptide release.

53. Renal salt and water retention, thereby restoring intravascular volume and triggering further leakage of fluid to the interstitium May cause : Ascites Rectal prolapse Pulmonary oedema Scrotal/labial pain intestinal edema/ defective absorption/malnutrition anasarca

54. Metabolic Consequences of Proteinuria Infections Hyperlipidimia , lipiduria and atherosclerosis Hypocalcemia and bone abnormalities Hypercoagulability Hypovolemia

55. 1. Infections -Low IgG levels due to impaired synthesis Decreased bactericidal activity of leukocytes ↑d losses of complement and properdin factor B, e.g. C3b needed for opsonization esp. of encapsulated organisms e.g. strep. Pneumoniae Edema /ascites as a culture media Malnutrition Immunosuppressive therapy ↓d perfusion of the spleen that acts as a filter organ.

56. 2. Hyperlipidemia and Lipiduria Due to ↑ hepatic lipoprotein synthesis triggered by reduced oncotic pressure - reactive hepatic protein synthesis. Compounded by increased urine loss of proteins that regulate lipid homeostasis i.e. lipoprotein lipase. LDL and cholesterol are ↑d due to ↑d synthesis, whereas VLDL and triglycerides tend to rise in patients with severe disease due to ↓d catabolism.

57. Hyperlipidemia may accelerate atherosclerosis and progression of renal disease. Lipiduria accompanies hyperlipidemia. Lipid in urine appears as free fat in urine, fatty casts or oval fat bodies(fat enclosed by plasma membrane of degenerative epithelial cells).

58. Conse cont’d Atherosclerosis due to hyperlipidemia may cause CKD or Hypertension. Transport protein loss e.g. Transferin – Microcytic anaemia (IDA). Cholecalciferol binding protein- Vit D deficiency, Hypocalcemia, & sec Hyperparathyroidism. Thyroxine binding globulin - ↓d thyroxine levels. Protein bound drugs changing their pharmacokinetics. Acute Kidney injury esp in older adults with minimal change disease and profound hypoalbuminemia.

59. 3.Hypocalcemia and Bone anomalies Usually caused by low serum albumin level Urinary loss of Vit D binding protein Reduced calcium absorption: gut edema , hypovitaminosisD Prolonged use of corticosteroids in management of NS.

60. 4. Hypercoagulability Caused by ↑d urinary loss of anticoagulants e.g. Antithrombin III, &proteins C and S, Hyperfibrinogenemia due to increased hepatic synthesis of Fibrinogen and Factors V, VII, VIII, X, ; Impaired fibrinolysis, Increased platelet aggregation due to hypovolemia & potential immobility. Patients can develop spontaneous peripheral arterial or venous thrombosis , renal vein thrombosis , and pulmonary embolism .

61. Management History: Body swelling- In dependent areas esp in early stage, e.g. periorbitally upon waking in morning, scrotal, labial regions.  Over the day, periorbital swelling decreases while that of the lower extremities increases. In the reclining position, localizes to the back and sacral area. Eventually, Generalised with abd’ distension & facial puffiness. Weight gain

62. Hx of infections both acute & chronic, e.g. pneumonia Hx of Drug use and Allergies. Symptoms related to the underlying Aetiology . Systemic symptoms + [malignancy / vasculitis] Symptoms related to complications above.

63. P/E Edema- pitting, soft, gravity dependent Fluid accumulation in body spaces e.g. ascites, pleural effusion & scrotal swelling Wasting masked with the edema. Hepatomegaly. Mild hypertension, most pts will have normal BPs. Abdominal pain. Dyspnoea – resp distress due to ascites. Signs of complications .

64. DDx CCF Hepatic failure Protein Malnutrition, - beriberi Other renal disorders- ARF, CRF Protein- losing enteropathies

65. Investigations. Laboratory Urine : Protein excretion measured on a 24 hr urine collection- Normal <150mg/day, Nephrotic range >3g/day. Alt- Total protein to creatinine ratio (PCR) on a random urine specimen of ˃2. Correlate closely with daily protein excretion in g/1.73m2 of BSA 2. Urinalysis (dipstick) + ve in >150-300mg/24hrs, 3. Microscopy – hematuria.

66. Investigations cont’d Blood : Albumin levels – U/E/Cs – dilutional hyponatremia Lipid profiles - ↑d LDL, total cholesterol & triglycerides. LFTs

67. CBC – Hb & HCT ↑d due to contracted plasma volume, leukocyte count may be normal even in infxns due to ↓d immune response, thrombocytosis may occur. RBS & HbA1c – r/o DM Serologic studies( if necessary): ANA, C3 C4, Anti-GBM

68. Investigations cont’d Renal Ultrasound Renal biopsy (Percutaneous) –define the pattern of glomerular involvement. -Determine Mngt decisions,

69. Indications. features suggestive of disease other than MCD Steroid resistant Frequent relapses or steroid dependency Significant chronic nephritis manifestations Adult nephrotic syndrome

70. Renal biopsy Contraindications Bleeding diathesis (uncorrectable) Severe HPTN- can’t be controlled Multiple bilateral cysts Renal tumour Hydronephrosis Active renal/ perirenal infection Unco-operative pt One kidney.

71. Treatment Supportive : Proteinuria -Lower intraglomerular pressure with reduction in protein excretion, may slow d’se progression ACEi or A 2 RB Note Initial K+ and serum creatinine Protein restriction-not usually done due to heavy protein loss Normal protein intake advised.

72. Rx cont’d 2. Edema: Dietary Na+, fluid restriction- low Na+ (~2g/d) diet Diuretics- Loop- Edema reversed slowly to prevent acute hypovolemia Serial Body weight measurements- evaluation of diuretic therapy. Aim ~1kg/day loss. Strict input/output charting

73. 3. Hyperlipidemia : Lipid abnorlities reverse with resolution of D’se HMG CoA reductase inhibitors – statins Dietary modification of little benefit Target LDL ~ 2.0 4. Hypercoagulability - Increased incidence of Art/ ven’ thromboembolism Prophylactic anticoagulation currently not recommended Avoid prolonged bed rest If Thrombosis occurs, Rx with heparin & Warfarin for as long as pt is nephrotic.

74. 5. Treat infections promptly. Pneumococcal vaccinations recommended. 6. Hypertension : Proteinuria is an independent risk factor for cardiovascular d’se. If >1g/d, target BP 125/75. Rx: ACE-I as 1 st line. Address risk factors: Smoking, Diet, Exercise.

75. 7. If on steroid chronically: Consider Ca2+, Vit D to reduce bone loss Septrin ( bactrim ) for PCP prophylaxis

76. Definitive Depend on underlying disorder (1 o )or cause (2 o ) Primary : 1. MCD - ~ 90% respond to steroids ~25%- long term remission ~25-30%- infrequent relapses ~20% - chronically relapse-Steroid dependant ~5%- steroid resistance (No response) 2. FGS - ~ 15% respond to steroids, others respond to immunosuppresive drugs-cyclosporine, cyclophpsphamide .

77. Rx cont’d 3. Membranous N- 5-30% spontaneous remission 25-40% partial remission (Prot<2g/d) Relapse rate: 30-50% but only 5% ESRD Renal survival- 86% at 5yrs,65% at 10yrs Poor prognostic factors: HPTN, Male, Elevated Cr Rx: Steroid+/-Chlorambucil or other immunosuppresants like Rituximab, mycophenolate mofetil .

78. Rx cont’d Induction therapy:   Exclude active infection or other contraindications prior to steroid therapy. Oral prednisone or prednisolone at 60 mg/m 2 /d (2 mg/kg/d) daily for 6 weeks. Maintenance therapy (following above induction therapy) Oral prednisone or prednisolone at 40 mg/m 2 (or 1.5 mg/kg) given as a single dose on alternate days for 6 weeks Following 6 weeks of alternate day treatment, steroids  slowly tapered over a variable length of time Relapse therapy For infrequent relapses, steroids are resumed, although for a shorter duration than treatment during initial presentation Prednisone 2 mg/kg/d (60 mg/m 2 /d) given as a single morning dose is administered until proteinuria has resolved for at least 2 days. Following remission of proteinuria, prednisone is reduced to 1.5 mg/kg (40 mg/m 2 ) given as a single dose on alternate days for 4 weeks. Steroids may then be gradually tapered

79. Prognosis The prognosis for patients with primary nephrotic syndrome varies depending on the histological type. Progressive renal insufficiency occurs in fewer than 1% of patients, and most deaths among patients with minimal-change glomerulonephritis are from infections and non-renal complications. Frequent relapses are more common with young age of onset and in boys.

80. THE END.