1. Nephrology Rounds Riki Buchwald, ID fellow December 17 th 2008

2. Case 46 y old AA man with h/o GSW to right trochanter in 8/07, s/p ORIF at OSH Admitted to Bellevue 9/07; found to have wound infection/OM with polyresistant Pseudomonas Extensive debridement performed but hardware left in place Underwent long-term treatment with polymyxin from 10/07 on. Course complicated by renal failure in 11/07 that resolved with polymyxin dose adjustment.

3. Case Hardware removed on 3/12/08 Wound cx with MRSA Received 4 week course of vancomycin and 6 week course of polymyxin after hardware removal; course completed at the end of April

4. Case Readmitted in 6/08 with increasing hip pain and persistent drainage Imaging c/w erosion of the right femoral head with joint space loss, septic arthritis and chronic osteomyelitis with sinus tract to the skin surface Debridement and washout performed on 6/18/08: OR cx grew MRSA Treated with vancomycin Developed worsening non oliguric renal failure with creatinine increase from 1.1 on admission to 6.8 mg/dl over 4 weeks

5. Clinical History  PMH: - Diabetes, A1c 7.9% in 10/2007 - HTN - Anemia - Remote h/o syphilis, treated  SH: no tobacco or drug abuse  Meds: insulin, lisinopril, iron, MVI, folic acid, omeprazole, escitalopram, cyclobenzaprine, SQ heparin  ROS: several weeks of darkened urine, leg swelling; denied: dysuria, macro-hematuria, SOB, fevers, joint pain, skin rash

6. Physical Exam  BP 150/89 HR 93 T 97.2 97% RA  Middle aged pt, appearing depressed, NAD  Sitting in wheelchair  Neck supple  Lungs: CTA  Heart: reg, nl S1 S2  Abdomen: soft, nontender  Right thigh with surgical scar, sutures in place, mild swelling and chronic skin changes, no frank drainage  Ext: b/l 3+ LE edema

7. Laboratory Data  Wbc 11.4, 73% PMN,18% Lymph, Eos WNL  Hgb 7.8  Plt 332  Hepatic: 42/64/201/0.2/8.2/3.4  Protein electrophoresis: TP 7.7, albumin 2.4  Globulins: alpha 1, alpha2, beta WNL, gamma 2.6 (0.5-1.3); diffuse bands

8. Laboratory Data CreatinineBUN 6/171.111 6/211.518 6/302.736 7/063.947 7/186.859 7/308.964  7/30: K: 5.2, Ca: 8.8, Phos: 6.0 Mg: 2.4  6/24: UA: protein >300 mg/dl, WBC 2-5,RBC packed, fine granular casts, RBC casts  7/02: Urine protein: 2g/day

9. Laboratory Data  HIV: negative  Hep B: SAb positive, SAg negative  Hep C: negative  Syphilis: IgG/TPPA positive, RPR negative

10. Any ideas?

11. A Diagnostic Test was Performed

12. Normal glomerulus

13. Nodular mesangial sclerosis

14. Crescentic necrotizing GN

15. RBC casts

16. IgAC3

18. Diagnosis Crescentic necrotizing glomerulonephritis with focal mesangial and subepithelial deposits (IgA and C3) Differential diagnosis: - IgA Nephropathy - post infectious GN - pauci-immune ANCA-associated GN - Methicillin-resistant Staphyloccocus post infectious GN

19. IgA nephropathy Postinfectious GN

20. Laboratory Data  C3: 172( 75-140); C4 28.5 (10-34)  ASLO: 57  ANA, ds DNA, ANCA: negative  Anti-GBM: negative  Urine immunofixation: negative

21. Final Diagnosis MRSA- post infectious GN

22. Objectives Postinfectious Glomerulonephritis (PIGN) Current trends in PIGN in adults Staphylococcus and IgA dominant PIGN

23. Postinfectious Glomerulonephritis Acute postinfectious GN (APIGN) = disease of childhood Commonly following a streptococcal infection (= APSGN) Clinical presentation: 3 phase sequence: infection - interval - nephritic syndrome Course of disease: 1 week: onset of diuresis 4 weeks: normalization of creatinine 3-6 months: resolution of hematuria; resolution of mesangial hypercellularity Years: resolution of proteinuria

24. APIGN: Histology Humps

25. APIGN: Outcome  Long term follow up studies: excellent prognosis for most children with the epidemic form  A Japanese study followed 138 children with non-epidemic form: None developed renal insufficiency, all had normal serum complement within 12 weeks, resolution of proteinuria within 3 yrs and hematuria within 4 yrs (Kasahara T et al, Pediatr Int 2001; 43: 364)  A 12-17 yrs f/u study of 534 children and adults in Trinidad showed complete recovery in 96.5% (Potter EV et al, NEJM 1982; 307: 725)  A 2005 study from Brazil studied 56 patients for 5.4 yrs who had APIGN related to an outbreak of Streptococcus zooepidemicus: 30% with HTN, 49 % with reduced GFR, 22% with microalbuminuria (Sesso R et al, Nephrol Dial Transplant 2005; 20:1808)  Literature reports recovery rate in adults 53-76%

26. APIGN: What is New in Adults? Retrospective studies:  Keller CK et al, Q J Med 1994; 87: 97 - Germany 1984-1993; 30 patients  Montseny JJ et al, Medicine 1995; 74: 63 - France 1976 - 1993; 76 patients  Moroni G et al, Nephrol Dial Transplant 2002; 17: 1204 - Italy 1979-1999; 50 patients  Nasr SH et al, Medicine 2008; 87: 21 - Columbia University 1995-2005; 92 patients

27. APIGN in Adults % of all renal biopsies: 0.6% - 4.6% Median age 49 - 58 yrs Underlying disease: 40-50% - Alcoholism +/- cirrhosis 2 - 57% - Diabetes 8 - 29% - COPD 7 - 33% - IVDU 3 - 27% - Malignancy 5 - 10% Moroni G et al 2002 No comorbidities + comorbidities

28. APIGN: Presentation  Nephritic syndrome: 60%  Nephrotic Syndrome: 30-50%  Mean serum creatinine: 1.5-6.4 mg/dl (  with comorbidities/crescentic GN)  Mean 24 hr-protein: 3.6 g (  with comorbidities) Endocapillary proliferation: 70-100% Crescents (> 20-30%) : 14 - 36% Interstitial infiltration: 30 - 80% ATN: 20 - 40% IF:  C3 deposits: 93 - 100%  C1: 18 - 35%  IgG deposits: 55 - 65%  IgM/IgA: 30 - 45% EM: Mesangial deposits: 33 - 90% Subendothelial: 44 - 75% Humps: 94 - 100%

29. Sites of Infection and Microbiology Streptococcus: 14-47% Staphylococcus: 12-24% Gram negatives: 1-22% 24-59% w/o microbiologic diagnosis Nasr et al: Mean latent period: 3 weeks 2 weeks (endocarditis), 3 weeks (SSTI), 4 weeks (URI) 8% of patients simultaneous diagnosis (20% of pt with endocarditis and 27% with PNA) URI: 24-44% SSTI: 5-25% Lung: 16-18% Endocarditis: 1-13% Dental: 0-13% UTI: 1-12%

30. Comorbidities and Histology No comorbidities With comorbidities Moroni G et al, Nephrol Dial Transplant 2002; 17: 1204

31. Outcome  CR 28-64% PRD 27-53% ESRD 4-17% Death 4-11%  Correlates of outcome: - CR: younger age, no underlying disease h/o URI endocapillary disease, no crescents or subendothelial deposits no interstitial inflammation - PRD: alcoholism nephrotic syndrome crescentic GN, interstitial fibrosis - ESRD: higher baseline creatinine underlying diabetic GS Nasr SH et al, Medicine 2008; 87: 21

32. % PIGN of all biopsies % complete remission % with severe interstitial infiltration % with “atypical” infection sites Moroni G et al, Nephrol Dial Transplant 2002; 17: 1204

33. Do Steroids Matter ? Montseny et al: 17 pt (12 with crescentic GN) treated with steroids, 8 additionally with cyclophosphamide: 2 died, 2 on HD, 3 with progressive CD, 5 with stable proteinuria, 5 with CR Moroni et al: CR or partial remission in 54% treated with steroids vs 72% of untreated (but pt with steroids with higher creatinine and interstitial inflammation) Nasr et al: 33% of 52 pt treated with steroids Indications: renal insufficiency with/without crescents CR in 12/17 patients with steroid therapy and 10/23 without (p=0.116) Nasr SH et al, Medicine 2008; 87: 21 Moroni G et al, Nephrol Dial Transplant 2002; 17: 1204 Montseny JJ et al, Medicine 1995; 74: 63

34. Staph and the Kidney 2 staphylococcal associated GN: - acute proliferative exudative GN associated with S. aureus endocarditis (resembling poststreptococcal GN) - membranoproliferative GN associated with S. epidermidis and ventricular shunt infections (“shunt nephritis”) Nasr SH et al, Hum Pathol 2003, 34: 1235

35. MRSA and PIGN In 1980, Spector et al first reported 3 pt with S. aureus visceral abscesses who developed acute mesangial proliferative GN with mesangial IgA deposits In 1995, Koyama et al reported 10 pt who developed a rapidly progressive GN with nephrotic syndrome associated with MRSA infections (abdominal 8, PNA 2, arthritis 1, phlegmon 1) Renal biopsy in 6 pt showed proliferative GN with various degrees of crescent formation and glomerular deposition of IgA, IgG and C3 Elevated serum IgA/IgG and immune complexes levels High number of T cells with V  + usage in the TCR: ? Superantigen driven event Named “MRSA Nephritis” or “Superantigen- related Nephritis” Spector DA et al, Clin Nephrol 1980; 14: 256 Koyama A et al, Kidney Internat 1995; 47: 207

36. MRSA and PIGN  Recent reports: similar features after MSSA and MRSE infections  Clinical presentation: - acute RF with hematuria, severe proteinuria - onset 2-16 weeks after infection - +/- purpura, +/- hypocomplementemia  Mostly mesangial proliferative GN, often with crescents and (pre-) dominant mesangial IgA deposits  Several cases do not have subepithelial humps, the “hallmark” of PIGN  Treatment of infection lead to resolution of GN; however 40-60% of pt developed ESRD  Steroid treatment was related to the death in 2 people but recent report suggest positive outcome if used after cure of infection Nagaba Y et al, Nephron 2002; 92: 297 Yoh K et al, Nephrol Dial Transplant 2000; 15: 1170 Shimizu Y et al, J Nephrol 2005; 18: 249 Okuyama S, Clin Nephrol 2008; 70: 344

37. Pathogenesis  Link between staphylococcal enterotoxins and T cell/cytokine activation?  Superantigen triggered cytokine activation leads to class switching to IgA?  Link to a staphylococcal cell wall antigen that co-localizes in glomeruli of patients with MRSA nephritis? Other IgA dominant immune responses against staphylococcal antigens? (eg an envelope antigen called ‘probable adhesin’ that is also found in IgA nephropathy) Nagaba Y et al, Nephron 2002; 92: 297 Yoh K et al, Nephrol Dial Transplant 2000; 15: 1170 Shimizu Y et al, J Nephrol 2005; 18: 249

38. Diabetes, Staph and the Kidney Nasr et al, Hum Pathol 2003; 34: 1235  In 2003, Nasr et al in New York reported 5 pt with DM who developed an IgA dominant GN after staphylococcal infection  Histology showed diabetic nephropathy with superimposed endocapillary proliferation with neutrophils and some degree of interstitial inflammation  IgA sole immunoglobulin in 3 cases; IF with mesangial or mesangial/capillary granular IgA and C3 staining  EM: all cases with predominantly mesangial deposits and sparse subepithelial deposits  Findings were similar to IgA nephropathy but all pt had low complement, endocapillary hypercellularity and humps

40. Endocapillary proliferation Subendothelial and subepithelial deposits Granular IgA Nodular sclerosis

41. IGA-PIGN vs IgA nephropathy IgA nephropathy:, IgA1 and J chain predominance? Nasr SH et al, Kidney International 2007; 71: 1317

42. Diabetes and IgA nephropathy  Increased serum levels of IgA and IgA immune complexes - secondary to (silent) mucosal infection - abnormal IgA clearance (abnormal glycosylation or sialylation)  Thickened BM and mesangial sclerosis hinders subepithelial deposit formation >> predominantly mesangial deposition Nasr SH et al, Kidney International 2007; 71: 1317

43. IgA predominant postinfectious GN Recently, Haas et al added 13 cases from John Hopkins University Selection criteria included IgA deposits + 3 or more subepithelial humps, no clinical history Not only associated with staphylococcal infection Haas M et al, Hum Pathol 2008; 39: 1309

44. Case follow-up  7/11: Proximal femoral osteotomy and acetabular excavation performed; antibiotic cement beads with vancomycin/tobramycin placed  On 7/17, vancomycin switched to linezolid given worsening renal failure  Creatinine slowly improved: 7/308.9 8/14 5.910/08 2.7

45. Summary Epidemiology of APIGN is shifting Diabetes, alcoholism and age emerge as major risk factor; prognosis is worse in pt with comorbidities and renal inflammation Microbiology is changing and staphylococci are increasingly important in APIGN Histologic pattern are changing, especially in immunocompromised persons

46. Summary IgA predominant APIGN is recognized as 3rd entity of staphylococcal associated GN IgA dominant PIGN can be associated with diabetic nephropathy Exact pathologic diagnosis and pathogenesis is still under debate This entity has to be differentiated from IgA nephropathy (and pauci-immune ANCA related GN) Treatment of infection can lead to recovery; however, pt with underlying diabetic GS have poor prognosis