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Nephrology Rounds

Detailed case study of a 46-year-old man with post-infectious glomerulonephritis following MRSA infection, including diagnosis, treatment, and long-term outcomes. Discussion on IgA-dominant PIGN and current trends in adults.

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Nephrology Rounds

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  1. Nephrology Rounds Riki Buchwald, ID fellow December 17th 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 • 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. IgA C3

  17. 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

  18. IgA nephropathy Postinfectious GN

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

  20. Final Diagnosis MRSA- post infectious GN

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

  22. 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

  23. APIGN: Histology Humps

  24. 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%

  25. 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

  26. No comorbidities + comorbidities 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

  27. 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% 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)

  28. 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% Sites of Infection and Microbiology

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

  30. 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 NasrSH et al, Medicine 2008; 87: 21

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

  32. 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) NasrSH et al, Medicine 2008; 87: 21 Moroni G et al, Nephrol Dial Transplant 2002; 17: 1204 Montseny JJ et al, Medicine 1995; 74: 63

  33. 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

  34. MRSA and PIGN • In 1980, Spector et alfirst 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 Vb+ 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

  35. 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

  36. 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

  37. Diabetes, Staph and the Kidney • 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 Nasr et al, Hum Pathol 2003; 34: 1235

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

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

  40. 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

  41. 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

  42. 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: 7/30 8.9 8/14 5.9 10/08 2.7

  43. 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

  44. 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

  45. Thanks!

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