IgA Nephropathy


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IgA Nephropathy

  1. 1. Dr Jishanth M Prof Dr A Gowrisankar’s Unit, M4
  2. 2. <ul><li>Mr A SHANMUGAM, 28 yr/M, </li></ul><ul><li>Unmarried, working in a shop, </li></ul><ul><li>admitted on 27-11-2007 with inability to speak, motor weakness of R UL and LL, preceded by 2 days h/o fever to a private hospital. </li></ul><ul><li>No h/o HTN/DM/Epilepsy </li></ul><ul><li>No family history of similar illness. </li></ul><ul><li>O/E patient was conscious, co-operative, disoriented at time, BP-120/80 mm Hg, all peripheral vessels are palpable, </li></ul><ul><li>(R) Hemiparesis+, Plantar ↑on R, ↓on L. </li></ul>
  3. 3. <ul><li>RBS 102 mg% </li></ul><ul><li>BU 35 </li></ul><ul><li>S Cr 1.2 </li></ul><ul><li>Na+ 135 </li></ul><ul><li>K+ 4 </li></ul><ul><li>TC 11200 </li></ul><ul><li>P82 L15 E3 </li></ul><ul><li>CXR showed f/o LRTI </li></ul><ul><li>ECG Normal </li></ul><ul><li>CT Scan showed Left MCA territory acute infarct and a small infarct in right parietal region. </li></ul>
  4. 5. <ul><li>Urine albumin+, </li></ul><ul><li>ANA negative, CRP negative </li></ul><ul><li>LFT normal </li></ul><ul><li>Total Cholesterol 255 mg%, TG 230, HDL 49, LDL 123, </li></ul><ul><li>IgM/IgG ACL Ab negative, </li></ul><ul><li>RA factor negative. </li></ul>
  5. 6. <ul><li>Patient was given anti-edema measures, Aspirin, Atorvastatin and other supportive therapies. </li></ul><ul><li>ECHO was normal, </li></ul><ul><li>Ultrasound abdomen showed mild splenomegaly, otherwise normal. RK 106/46mm, LK 111/43mm, Corticomedullary echo pattern normal. </li></ul><ul><li>HIV- negative. </li></ul><ul><li>Thrombophilia profile- normal </li></ul><ul><li>Patient improved, apparently normal, started walking, continued atorvastatin/aspirin. </li></ul>
  6. 8. <ul><li>6 months later patient developed hypertension, for which he was started on Ramipril, </li></ul><ul><li>BU 36, S Cr 1.28, </li></ul><ul><li>Urine Alb 1+. </li></ul>
  7. 9. <ul><li>One year after the stroke, patient developed facial puffiness and was evaluated for renal cause. </li></ul><ul><li>BU 42, S Cr 1.8 </li></ul><ul><li>Urine showed albumin 3+ </li></ul><ul><li>24 hr urine protein 5.5 g/day </li></ul><ul><li>Ultrasonogram- normal sized kidneys </li></ul><ul><li>Medical Renal disease+, Splenomegaly+ </li></ul><ul><li>Dopplerstudy of renal arteries normal </li></ul><ul><li>Serum Calcium- 8.1 mg% </li></ul><ul><li>Serum Uric Acid 6.9 mg% </li></ul>
  8. 10. <ul><li>FBS 90/ PPBS 118, Urine sugar-negative </li></ul><ul><li>ANA neg, CRP neg </li></ul><ul><li>HIV neg </li></ul><ul><li>HBsAg neg, Anti HCV negative </li></ul><ul><li>PT 11.7s(12s), aPTT 20s(30s) </li></ul><ul><li>IgG/IgM ACL Ab negative </li></ul><ul><li>CXR normal, ECG normal </li></ul><ul><li>Peripheral smear study -normal. </li></ul><ul><li>Patient underwent renal biopsy which showed segmental sclerosis with mesangial proliferation, focal tubular atrophy, and Immunofluroscence showed mesangial and peripheral deposits in IgA, C3c and IgM with fibrinogen. </li></ul>
  9. 11. <ul><li>Patient was given diuretics and steroid. Elevated renal parameters came down, BU 28, S Cr 1.1. </li></ul><ul><li>Patient continued Ramipril, Atorvastatin, Aspirin. </li></ul><ul><li>Patient was put on prednisolone. </li></ul>
  10. 13. <ul><li>After 3 months RBS 238, BU 32, S Cr 1.3, </li></ul><ul><li>BP 110/90 mmHg, </li></ul><ul><li>Serum total protein 5.8 g%, Alb 3.8, Globulin 2g </li></ul><ul><li>Urine albmin 3+. </li></ul><ul><li>Steroids were slowly tapered off. </li></ul><ul><li>Sugar levels came down. </li></ul><ul><li>BP was fluctuating. </li></ul>
  11. 14. <ul><li>2 years after the initial stroke, patient developed swelling of left lower limb associated with pain, </li></ul><ul><li>Doppler study showed left popliteal vein thrombosis extending upto adductor canal, </li></ul><ul><li>Blood Sugar 99, BU 28, S Cr 1.2 </li></ul><ul><li>Na+ 138, K+ 3.9 </li></ul><ul><li>CX- normal </li></ul><ul><li>Urine albumin 2+ </li></ul><ul><li>Cholesterol 182 </li></ul><ul><li>S Total protein 5.9 g, Albumin 3.7, Glob 2.2. </li></ul><ul><li>Patient again readmitted and continued Atorvastatin, Prednisolone, Ramipril, +Acitrom 3 mg OD. </li></ul>
  12. 15. <ul><li>At discharge 24 hr urine protein was 1.7g, </li></ul><ul><li>BP 140/90 mmHg, </li></ul><ul><li>Protein C 42.3(70-140), </li></ul><ul><li>Protein S 54.9(60-150), </li></ul><ul><li>Serum Homocysteine 16.50(5.9-16), </li></ul><ul><li>Anti thrombin III level-normal. </li></ul><ul><li>He was discharged with advice to continue aspirin, atorvastatin, ramipril, acitrom, and prednisolone. </li></ul><ul><li>After 3 months 24 hr urine protein was 360 mg and steroid was slowly tapered. </li></ul><ul><li>BU 27, S Cr 0.7, RBS 92 mg%. </li></ul><ul><li>Ultrasonogram-no splenomegaly. </li></ul>
  13. 18. <ul><li>Scanty glomeruli with sclerosing proliferative glomerulonephritis, focal tubular atrophy and abundant IgA deposits, consistent with </li></ul><ul><li>“ IgA Nephropathy” </li></ul>
  14. 19. <ul><li>To rule out remote possibilities of pauci-immune glomerulonephritis, ANCA antibodies were done- both were negative. </li></ul>
  15. 23. <ul><li>It is the commonest form of glomerulonephritis resulting in ESRD throughout the world </li></ul><ul><li>also known as </li></ul><ul><li>IgA nephritis, </li></ul><ul><li>Berger's disease , </li></ul><ul><li>Synpharyngitic glomerulonephritis </li></ul><ul><li>Prevalence 25-50/1,00,000 </li></ul><ul><li>Male preponderence, peaks in 2/3 rd decade </li></ul><ul><li>Rare familial clustering </li></ul>
  16. 24. <ul><li>Signs and symptoms </li></ul><ul><li>classic presentation ( 40-50% ) is </li></ul><ul><li>episodic frank haematuria after URTI (synpharyngitic) or </li></ul><ul><li>microscopic haematuria </li></ul><ul><li>microscopic haematuria and proteinuria (20-30%) </li></ul><ul><li>nephrotic syndrome(5%) </li></ul><ul><li>acute renal failure(5%) </li></ul><ul><li>chronic renal failure(5%) </li></ul>
  17. 25. <ul><li>Immunohistochemical findings of mesangial deposition of IgA </li></ul><ul><li>light microscopy: mesangial cell proliferation is the commonest feature </li></ul><ul><li>What is “MEST”…Global IgA Consortium Project* </li></ul><ul><li>• Mesangial proliferation 0/1 </li></ul><ul><li>• Endocapillary proliferation 0/1 </li></ul><ul><li>• Segmental sclerosis/adhesion 0/1 </li></ul><ul><li>• Tubular atrophy /interstitial fibrosis 0/1/2 </li></ul>
  18. 26. <ul><li>indolent progressive nature </li></ul><ul><li>15% to 40% of adults and children will progress to ESRD </li></ul><ul><li>15 to 20% develop ESRD within 10 years of onset </li></ul><ul><li>30 to 35% develop ESRD within 20 years of onset </li></ul>
  19. 28. <ul><li>Deposits of Immunogloblin A (IgA) in a blotchy pattern in the mesangium (on immunofluroescence), the HEART of the renal glomerulus </li></ul><ul><li>The tissue changes gradually from being hypercellular to depositing extracellular matrix proteins, and finally fibrosis </li></ul>
  20. 29. <ul><li>A recently advanced theory focuses on abnormalities of the IgA1 molecule. IgA1 is one of the two immunoglobulin subclasses that is O-glycosylated on a number of serine and threonine residues in a special proline-rich hinge region. </li></ul><ul><li>Deficiency of these sugars appears to lead to polymerisation of the IgA molecule in tissues, especially the glomerular mesangium. </li></ul><ul><li>IgAN can recur after renal transplant - caused by a problem in the immune system rather than the kidney itself. </li></ul>
  21. 30. Immunofluorescence Periodic acid-Schiff stain
  22. 31. <ul><li>Genetic factors </li></ul><ul><ul><li>Chr 6q 22-23 </li></ul></ul><ul><li>Aberrancy of structure of IgA1 molecules </li></ul><ul><ul><li>Glycosylation aberrancy -> aggregation, CIC formation, </li></ul></ul><ul><li>Increased levels of IgA and IgA-containing complexes </li></ul><ul><ul><li>Overproduction or defective clearance </li></ul></ul><ul><li>Endogenous or exogenous antigens </li></ul><ul><ul><li>CIC formation, IgA renal deposition </li></ul></ul><ul><li>Immunological defects </li></ul><ul><ul><li>(allergy, complement, coagulation, ...) </li></ul></ul><ul><ul><li>“ AUTOIMMUNE DISEASE” </li></ul></ul>
  23. 32. <ul><li>Genetic aspects (Progression) </li></ul><ul><li>ACE gene polymorphism </li></ul><ul><li>Angiotensinogen gene polymorphism </li></ul><ul><li>High Blood Pressure and persistant level of proteinuria are the major (known) independent determinants of progression </li></ul>
  24. 33. <ul><li>Conservative </li></ul><ul><li>Blockers of the renin-angiotensin system </li></ul><ul><li>Corticosteroids </li></ul><ul><li>Fish oil (n-3 Polyunsaturated Fatty Acids) supplementation </li></ul><ul><li>Cyclophosphamide </li></ul><ul><li>Mycophenolate mofetil (MMF) </li></ul>
  25. 34. <ul><li>CONSERVATIVE TREATMENT </li></ul><ul><ul><li>normal renal function, </li></ul></ul><ul><ul><li>normotension and </li></ul></ul><ul><ul><li>only minor urinary abnormalities </li></ul></ul><ul><ul><ul><li>isolated microscopic haematuria, and/or </li></ul></ul></ul><ul><ul><ul><li>mild proteinuria </li></ul></ul></ul><ul><ul><li>keep such patients under review </li></ul></ul><ul><ul><li>Up to 23% of patients will have a spontaneous complete remission . </li></ul></ul>
  26. 35. <ul><li>BLOCKERS OF THE RENIN-ANGIOTENSIN SYSTEM </li></ul><ul><li>Reduction in proteinuria is considered to be the hallmark of effective treatment in preserving renal function in nondiabetic renal diseases. </li></ul><ul><li>ACEi and more recently angiotensin II type 1 receptor blockers (ARB) control blood pressure and proteinuria </li></ul><ul><li>Controls both proteinuria and hypertension(modifiable risk factors for progression of disease) </li></ul><ul><li>Superior to other antihypertensive drugs in lowering proteinuria by virtue of their capacity to reduce intraglomerular pressure. </li></ul>
  27. 36. <ul><li>CORTICOSTEROIDS </li></ul><ul><li>Steroid does not appear to consistently offer any beneficial effect other than modest amelioration of proteinuria. </li></ul><ul><li>The only exception is in children with IgA deposition in the setting of minimal change nephrotic syndrome. Such patients respond to corticosteroid promptly. </li></ul><ul><li>In adults, in view of the toxicities associated with steroid therapy, it should be considered only when proteinuria persists >1 g/24 h despite optimal BP control and maximum RAS blockade. </li></ul>
  28. 37. <ul><li>Fish oil (n-3 Polyunsaturated Fatty Acids) supplementation </li></ul><ul><li>The rationale of using fish oil in IgAN is based on the premise that n-3 PUFAs alter the production or action of cytokines and eicosanoids evoked by the initial or repeated immunological renal injury, alleviating ongoing renal inflammation and glomerulosclerosis (hallmarks of progressive renal disease) </li></ul><ul><li>Mayo investigators published their long-term data in 1999 to conclude that early and prolonged treatment with fish oil slows renal progression for high-risk patients with IgAN. </li></ul><ul><li>Still under debate. </li></ul>
  29. 38. <ul><li>CYCLOPHOSPHAMIDE </li></ul><ul><li>Cytotoxic agent </li></ul><ul><li>Only if high risk for progression to ESRD </li></ul><ul><li>Only one study suggested efficacy of cyclophosphamide followed by azathioprine in conjunction with high-dose prednisolone in patients who are at very high risk for progression (ESRD predicted in all cases within 5 yr). (Ballardie ) </li></ul><ul><li>Insufficient evidence to justify the use in IgAN except in crescentic IgAN with rapidly progressive renal failure </li></ul>
  30. 39. <ul><li>Mycophenolate mofetil (MMF) </li></ul><ul><li>The rationale is its selective suppressive effects on lymphocyte proliferation and antibody formation </li></ul><ul><li>Hong Kong data showed that a 6-month course of MMF (0.75 to 1 g b.d.) can induce lasting remission (up to 72 weeks of follow up ) of proteinuria in at risk patients (i.e. those with persistent proteinuria >1g/day despite full RAS inhibition and normal BP, but had histology that did not reveal advanced sclerosis). ( Tang S ) </li></ul><ul><li>Beijing data suggested that MMF is more effective than prednisone in reducing proteinuria in patients with urinary proteinuria > 2 g/d. ( Chen X ) </li></ul>
  31. 40. <ul><li>Male gender </li></ul><ul><li>proteinuria (especially > 2 g/day), </li></ul><ul><li>hypertension </li></ul><ul><li>smoking </li></ul><ul><li>hyperlipidaemia </li></ul><ul><li>older age </li></ul><ul><li>familial disease </li></ul><ul><li>elevated serum creatinine </li></ul><ul><li>kidney biopsy: interstitial scarring </li></ul>
  32. 41. Risk factors for ESRD
  33. 43. <ul><li>Harrison’s Principles of Internal Medicine: 17ed </li></ul><ul><li>Proteinuria:How to evaluate an important finding: WAQAR KASHIF, MD Department of Medicine, Medical College of Wisconsin,Milwaukee(Review ) </li></ul><ul><li>IgA nephropathy:The Value of Proteinuria, Daniel Cattran,CNC-ASN,Philadelphia, PA,2008 </li></ul><ul><li>UpToDate 17.1 </li></ul>