Acute Nephritic Syndromes

Acute Nephritic Syndromes

1. Acute Nephritic Syndrome CHAIR PERSON : DR MAHABALESHWAR MAYYA STUDENT : DR RaVIKIRAN NHRMC IM

2. Introduction Clinical presentation of nephritic syndrome includes Acute nephritic syndrome, Syndrome of rapidly progressive glomerulonephritis, Syndrome of chronic glomerulonephritis

3. Introduction

4. Introduction Acute nephritic syndromes classically present with the following: Hematuria Subnephrotic proteinuria ( 1- 2 g/24 h ) Hypertension Fluid retention Red blood cell casts Pyuria Rise in serum creatinine Reduction in GFR

5. Acute Nephritic Syndromes

6. Acute Nephritic Syndromes

7. Causes according to age CHILDREN AND ADOLESCENTS Post-streptococcal glomerulonephritis MPGN Cresentic GN IgA nephropathy Lupus Nephritis Henoch-Schönlein purpura ADULTS IgA Nephropathy Rapidly progressive glomerulonephritis SLE or lupus nephritis ANCA associated Membranoproliferative GN Hepatitis B or C Infective endocarditis Abdominal abscesses Viral diseases such as mononucleosis, measles, mumps

8. INFECTIOUS CAUSES OF ACUTE NEPHRITIS Infectious syndromes Specific bacterial diseases Mycobacterial, rickettsial , mycoplasmal , chlamydial, and spirochetal diseases Fungal infections Viruses Parasitic infestations NON-INFECTIOUS CAUSES OF ACUTE NEPHRITIS Immune mediated glomerulonephritis Immune complex GN IgAN,HSP,LN … ANTI-GBM GN GPS,Anti -GBM ANCA associated GN MP,WG,CSS Kanjanabuch , T. et al. Nat. Rev. Nephrol . 5, 259–269 (2009); doi:10.1038/nrneph.2009.44

9. SITE OF INJURY IN ACUTE NEPHRITIC SYNDROME

10. APPROACH

11. CLINICAL APPROACH (POST-INFECTIOUS) On the background of Acute Nephritis features…. 5 and 12 years (90%) and >40(10%) boys > girls Pharyngitis(1-3) Impetigo(2-6) may be severe enough to appear as RPGN Constitutional symptoms - as many as 50% of cases IVDU Cardiac murmur Dental abscess.Osteomyelitis,deep seated abscesses Treated hydrocephalus PSGN Endocarditis Shunt Abscess

12. IMMUNE MEDIATED GLOMERULONEPHRITIS IMMUNE COMPLEX GN ANTI-GBM GN ANCA ASSOCIATED GN

13. IMMUNE COMPLEX GN On the background of Acute Nephritis features…. 20s and 30s men > women asymptomatic microscopic hematuria most often seen in adults Recurrent synpharyngitic gross hematuria No vasulitis Asso with systemic diseases <20 years of age (4-7) Macroscopic haematuria - time of infections Purpuric rash, arthritis, abdominal pain (Systemic vasulitis ) Young women in 20 and 30s Arthralgia , photosensitive skin rash, pleurisy , and pericarditis 5 - 12 years boys > girls Acute Strept infection(1-6 weeks before presentation ) MPGN I MPGN II MPGN III IgA Nephropathy HSP Lupus Nephritis Acute PSGN MPGN

14. MPGN 20s ; women > men Systemic symptoms - most common Asso – HepC,Cryogloulin,neoplasias Teenage ; women > men Gaunt face due to partial Lypodystrophy 20s women > men MPGN I MPGN II MPGN III Middle age Abnormal LFT (rarely cirrhosis), pupuric rash, neuropathy,polyarthralgia , leg ulcers MPGN I with Hep C

15. ANTI-GBM GN On the background of Acute Nephritis features…. Young men(late 20s) both sexes (50s and 70s) With lung haemorrhage GPS 20s:Young men; 50s and 60s:both sexes Without lung haemorrhage Anti-GBM GN

16. ANCA ASSOCIATED GN With the background of Acute Nephritis features…. 50s/60s men = women Weight loss, malaise, LRT symptoms, arthritis , palpable purpura no Asthma 50s/60s men = women Weight loss, malaise, URT/LRT symptoms, arthritis , palpable purpura no Asthma 20-40 Males>females Asthma Neuropthy Microscopic Polyangitis Wegeners Granulomatosis CSS

17. LABORATORY APPROACH

18. DARK URINE DIPSTICK FOR HEME NEGATIVE DRUGS FOOD DYES MELANIN POSITIVE GROSS HEMATURIA MICROSCOPIC HEMATURIA TRAUMA PRESENT TRAUMA ABSENT IMAGING OF ABDOMEN AND PELVIS CYSTOSCOPY PAINFUL PAINLESS URINE CALCIUM URINE CULTURE RENAL CALCULI U.CA FAMILIAL( Alports ) HSP HB ELECTRO EUMORHIC RBCs DYSMORHIC RBCs U.CA R/O MEATAL STENOSIS FAMILY SCREENING(Thin GBM) W/U FOR GLOMERULONEPHRITIS NO RBCs HB,MB

19. Photomicrograph of urine sediment with a red cell cast Phase contrast micrograph showing dysmorphic red cells in urine sediment Scanning electron micrograph showing dysmorphic red cells in urine sediment

20. INVESTIGATIONS

21. POST-INFECTIOUS GN Anti streptolysin titre anti- DNAse B Throat swab or skin swab 2D ECHO TEE USG X-ray VP shunt evidence PSGN Endocarditis Shunt Abscess OTHER SPECIFIC INVESTIGATIONS

22. IMMUNE COMPLEX GN Glomerular immune complex localisatIon with granular capillary wall and/or mesangeal staining Raised serum IgA in 50% of cases , Leucocytoclastic vasulitis antinuclear antibody/ anti-ds DNA, anticardiolipin antibody antistreptolysin titre MPGN I MPGN II MPGN III IgA Nephropathy HSP Lupus Nephritis Acute PSGN MPGN OTHER SPECIFIC INVESTIGATIONS

23. MPGN Low C4 (classical path activation) Low C3 (alternative path activation), C3 nephritic factor Dense deposits Complement receptors defect MPGN I MPGN II MPGN III Low C4, + ve hepatitis C serology, hepatitis C RNA on PCR , serum cryoglobulins , + ve antinuclear antibody/ + ve Rh factor MPGN I with Hep C OTHER SPECIFIC INVESTIGATIONS

24. ANTI-GBM GN Circulating Anti-GBM antibodies with linear GBM staining for IgG With evidence of lung haemorrhage GPS Without lung haemorrhage Anti-GBM GN OTHER SPECIFIC INVESTIGATIONS

25. ANCA ASSOCIATED GN Circulating ANCA with paucity of glomerular immunoglobulin staining P-ANCA(MPO) Vasculitis with no granuloma No cavities C-ANCA(RP3) Granulomas Cavitations P-ANCA(MPO) Eosinophilia Granuloma Microscopic Polyangitis Wegeners Granulomatosis CSS OTHER SPECIFIC INVESTIGATIONS

26. PIGN/IRGN

27. ACUTE POST-STREPTOCOCCAL GLOMERULONEPHRITIS AGN that follows an infection with a nephritogenic strain of group A beta hemolytic streptococci. The classic example of the acute nephritic syndrome. Incidence of clinically detectable glomerulonephritis during an epidemic is up to 10% of children with pharyngitis and 25% of children with impetigo Nelson Textbook of Pediatrics , 7th Edition

28. Streptococcal infection of the throat or skin ( impetigo)

29. EpidEmiology Globally - incidence has decreased in the past three decades . Throat (serotype 12) - cold weather months. S kin (serotype 49) - warm weather months. BUT Most commonly – sporadic. Despite that, epidemics and clusters of cases – in some poor or rural communities (© 2008 American Society of Nephrology ) Peak incidence - age 5-12 y/o, uncommon <3y/o. Male : female ratio is 2 : 1 . Nelson Textbook of Pediatrics , 7th Edition

30. Clinical course Spontaneous improvement typically begins within 1 wk R esolution of edema in 5-10 days Hypertension in 3-4 wk Proteinuria -- normalize by 4-6 wk Acute phase resolves within 6-8 wk Urinalysis may be abnormal ( persistent microscopic hematuria ) upto a year

31. Antibodies to streptococcal antigen(s) Anti- streptolysin O titer (ASOT) >333 TOD Units COMMONLY elevated after a pharyngeal infection but RARELY increases after streptococcal skin infections Anti deoxyribonuclease ( DNase ) B antibodies best single antibody titer to document cutaneous streptococcal infection Anti- hyaluronidase antibodies Anti-streptokinase antibodies

32. IndIcatIons for renal BIopsy Severe acute renal failure requiring dialysis. Features suggesting non post-infectious AGN as the cause of acute nephritis . Absence of the latent period between streptococcal infection and acute glomerulonephritis Normal complement levels initially in early course Persistence of low C3 beyond 6-8 wks Delayed resolution Oliguria > 2 weeks Azotaemia > 3 weeks Gross haematuria > 3 weeks Persistent proteinuria > 6 months

33. lIght mIcroscope (not specIfIc for post streptococcal nephrItIs ) Glomeruli - enlarged,hypercellular . Diffuse mesangial cell proliferation Increase in mesangial matrix . PMNs - common in glomeruli Crescents and interstitial inflammation

34. PSGN.. Immunofluorescence microscopy Lumpy-bumpy deposits of immunoglobulin Complement Glomerular basement membrane ( GBM) Mesangium Electron microscopy Electron-dense deposits, or "humps," on the epithelial side of the GBM

35. management Treatment is supportive control of hypertension, edema, and dialysis as needed. Strict monitoring – I/O/weight/BP Penicillin V for 10 days to eliminate β - haemolytic streptococcal infection ( give erythromycin if penicillin is contraindicated) patients C ohabitants( if culture positive for GAS ) NOTE : Antibiotic therapy does not affect natural history of glomerulonephritis

36. Management… Diet – no added salt to diet,Protein restriction is unnecessary No role for immunosuppressive therapy(even in the setting of crescents) FOLLOW UP: Recheck serum complement at 6-8 wks . C heck BP, renal function test and urinalysis every 1-3 month for 1 yr then yearly

37. complIcatIons Hypertensive encephalopathy usually presenting with seizures Pulmonary oedema (acute left ventricular failure ) Acute renal failure

38. Poor prognosis indicated in … (PSGN) History of childhood PSGN Older age. History of massive proteinuria. History of Alcoholism or drug abuse. Underlying disease such as Diabetes, Cardiovascular and liver disease. Persistent abnormal renal function. History of dialysis at presentation. Biopsy feature(including crescent)

39. ouTcoME Short term outcome: Excellent, mortality <0.5%. RPGN – 4.6% Long term outcome: 1.8 % (1-3%) of children develop chronic kidney disease Complete resolution  within 3–6 weeks Complete recovery >95% of children 60 % of adult .

40. VariantS of PIGN Staphylococcus associated GN. Associated with ventrilovascular shunt, IE . Some resemble IgA nephropathy. HBV associated GN. HIV associated GN such as HIVAN O ther infection associated GN

41. GN associated with IE Incidence range from 22-78 %. Highest among IV drug abusers Particularly in patients who: Remain untreated for an extended period of time Have negative blood cultures Have right-sided endocarditis (IVDU ) Grossly, subcapsular hemorrhages with a "flea-bitten" appearance Most typical finding is focal and segmental proliferative GN . Primary treatment is eradication of the infection with 4–6 weeks of antibiotics Prognosis is good.

42. Shunt nephritis related GN Immune mediated complex GN. Complication of chronic infection via ventriculovascular shunts , common in treatment of hydrocephalus . In contrast to vascular shunt, VP shunt rarely developed GN. Typical type I MPGN (deposit - mesangial and subendothelial ). Typical organisms are Staphylococcus spp

43. HCV infection related GN HCV frequently causes extrahepatic manifestation. Kidney involvement… Most common associated with type II cryoglobulinemia .(1) Type I MPGN ( Cryoglobulin deposits). Best long term prognostic indicator is HCV with SVR. RNA clearance from serum at least 6 month. Paucity of controlled study in HCV associated GN. Rituximab plus Peg-interferon a2b and Ribavarin show good response in stabilized kidney function in cryoglobulinemic vasculitis (2) (1) Chapter 9; Infection-related GN. Kidney International Supplements (2012) 2, 200–208 (2) Saadoun D, Resche-Rigon M, Sene D et al. Rituximab combined with Peg-interferon-ribavirin in refractory HCV - cryoglobulinaemia vasculitis . Ann Rheum Dis 2008; 67: 1431–1436.

44. HBV infection related GN Pattern of kidney involvement included. MN is the most common form, especially in children. Other such as MPGN, FSGS and IgAN . Exclude other cause of GN first. Prognosis … – In children  high spontaneous remission. – In adult  usually progressive, especially with abnormal LFT and nephrotic syndrome, >50% progressing to ESRD. Treat HBV infection( Ente,Lami,Teno,Adefovir ) Currently no data about efficacy of treatment in HBV- related GN.

45. HIV related GN Variety spectrum of kidney disease. HIVAN is the most common cause of CKD in HIV-1. APOL1 gene related. Typical collapsing FSGS on pathology. HAART is beneficial in both preservation and improvement in kidney function. N ot effective in other GN associated with HIV infection. ACE-I may benefit in HIV with nephrotic syndrome

46. Schistosomal nephropathy S.Mansoni and S.japonicum , blood fluke. Incidence is not well defined. Y oung adult males. Commonly seen eosinophiluria (65%) and hypergammaglobilinemia (30%). Aware co-infection with salmonella,Especially in Hepatosplenic involvement . Once established GN, currently no effective therapy. None of immunosuppresant recommended. Prevent by Praziquantel or Oxamiquine

47. Filarial nephropathy Loa loa , Onchocerca volvulus, W. bancrofti and B. Malayi . Immune mediated from worm antigens. Urinary abnormalities have been reported 11-25%. Nephrotic syndrome 3-5%, concomitant with polyarthritis and chorioretinitis . Especially in lymphatic filariasis . Can induce diffuse GN and MPGN, MPGN, MND or Sclerosing GN. Treat by Ivermectin or Diethylcarbamazine .

48. Malarial nephropathy P.Falciparum . May resulted in AKI or proliferative GN. P.Malariae . Variety of kidney disease especially MN or MPGN. Currently no RCT for evidence base treatment. Suggestion only appropriate anti-Malarial agent

49. I g A nephropathy ( I g AN ) Berger's disease/ Synpharyngitic glomerulonephritis MC type of GN worldwide Male preponderance Peak incidence in the 2 nd and 3 rd decades Recurrent painless gross hematuria . Preceded by (usually 1-3 days ) infections(URTI,GE). Defined by the presence of diffuse mesangial IgA deposits often associated with mesangial hypercellularity .

50. I g A Nephropathy Deposits of IgA are also found in the glomerular mesangium in a variety of systemic diseases, including: Chronic liver disease Crohn's disease Gastrointestinal adenocarcinoma Idiopathic interstitial pneumonia Dermatitis herpetiformis Mycosis fungoides Leprosy Ankylosing spondylitis

51. IgA - polymeric forms Only IgA1 forms the nephritogenic deposits A genetic or acquired abnormality of immune regulation leading to increased IgA synthesis in response to respiratory or gastrointestinal exposure to environmental agents HTN & renal insufficiency --- uncommon 30% to 40% have only microscopic hematuria , with or without proteinuria 5 % to 10% develop a typical acute nephritic syndrome

52. Pathogenesis- Secondary IgA nephropathy IgA nephropathy occurs with increased frequency gluten enteropathy (celiac disease), in whom intestinal mucosal defects are well defined liver disease , in which there is defective hepatobiliary clearance of IgA complexes (secondary IgA nephropathy ) . Alternatively, there is evidence for qualitative alterations in the IgA1 molecule itself

53. I g AN IgA nephropathy is typically an isolated renal disease, similar IgA deposits are present in a systemic disorder of children , Henoch-Schönlein purpura which has many overlapping features with IgA nephropathy . In addition, secondary IgA nephropathy occurs in patients with liver and intestinal diseases

54. I g AN ..Clinical course The hematuria typically lasts for several days and then subsides, only to return every few months. The subsequent course is highly variable Many patients maintain normal renal function for decades. Slow progression to chronic renal failure occurs in 15% to 40% of cases over a period of 20 years Recurrence of IgA deposits in transplanted kidneys is frequent

55. I g AN … Clinical course Clues to an increased risk of progression(loss of renal function) Onset in old age Heavy proteinuria Hypertension Extent of glomerulosclerosis on biopsy A bsence of episodes of macroscopic hematuria, male

56. I g A Nephropathy Angiotensin-converting enzyme (ACE) inhibitors in patients with proteinuria or declining renal function. When presenting as RPGN, patients typically receive: Steroids Cytotoxic agents Plasmapheresis

57. C3 glomerulonephritis

58. INTRODUCTION MPGN- not a diagnosis per se Rather a histopathologic pattern of injury See for potential underlying causes of injury Clinical classification Idiopathic or primary Secondary Primary MPGN – based on ultrastructural appearance and location of electron-dense deposits Type I Type II Type III

59. DDD was renamed MPGN2 in 1975 Now considered inappropriate to refer to DDD as MPGN2 Pathological pattern of MPGN is absent in the majority of cases of DDD .

60. Summary of clinical and laboratory features of C3 glomerulopathies

61. Management Predictors of outcome Renal dysfunction – Sr Cr, GFR Proteinuria DDD- older age at diagnosis - an independent predictor of ESRD C3GN may have a more benign course than patients with DDD

62. Treatment Targeted therapies have not proven to be universally beneficial – Heterogeneity of the C3 glomerulopathies Control of alternative complement pathway activity Replacement of factor H - viable option Pts with genetic defects of inhibitory proteins of the alternative complement pathway - replacement of factors

63. Treatment… Replacement Plasma exchange Pharmaceteucal preparation (not available at present) Replacement not successful in certain pts Mutant C3 convertase that is resistant to factor H Control Pts with an acquired antibody to an inhibitory protein of the alternative pathway Immunosuppressive therapy Corticosteroids mycophenolate mofetil rituximab Eculizumab Humanized monoclonal antibody to C5 Prevents the generation of the MAC

64. C3 GN vs DDD C3GN have a slightly better prognosis than do pts with DDD DDD – progression to ESRD 25 % after 5 years 50 % after 10 years from diagnosis French cohort - C3 glomerulopathy ¼ th of adult pts with C3GN progressed to ESRD over 10 years of f/u American cohort - C3GN No significant decline in renal function over a mean follow-up of 26 months

65. References Harrisons Principles of Internal Medicine – 19 th Edition Brenner and Rector – The Kidney – 9 th Edition Comprehensive Clinical Nephrology - John Feehally , Richard J. Johnson, Jürgen Floege – 5 th edition Nelson Textbook of Pediatrics , 7th Edition Acute glomerulonephritis ; C S Vinen, D B G Oliveira: Postgrad Med J 2003;79:206–213 An update on acute postinfectious glomerulonephritis worldwide Talerngsak Kanjanabuch , Wipawee Kittikowit and Somchai Eiam-Ong - Nat. Rev. Nephrol . 5, 259–269 (2009); doi:10.1038/nrneph.2009.44 INCIDENCE OF ACUTE POST STREPTOCOCCAL GLOMERULONEPHRITIS IN CHILDREN doi:10.1136/archdischild-2012-302724.1205

66. References The Korean Society of Nephrology - New Classification of MPGN/Kidney Res Clin Pract 33 (2014)171–173 http://dx.doi.org/10.1016/j.krcp.2014.10.005 WG Couser and RJ Johnson : The etiology of glomerulonephritis: roles of infection and autoimmunity - Kidney International (2014) 86, 905–914; doi:10.1038/ki.2014.49 Chapter 9; Infection-related GN. Kidney International Supplements (2012) 2, 200–208 Saadoun D, Resche-Rigon M, Sene D et al. Rituximab combined with Peg-interferon-ribavirin in refractory HCV - cryoglobulinaemia vasculitis . Ann Rheum Dis 2008; 67: 1431–1436

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