Nephrology Rounds

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Nephrology Rounds

• Riki Buchwald, ID fellow
• December 17th 2008

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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.

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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

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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

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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

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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

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Laboratory Data

• 7/30 K 5.2, Ca 8.8, Phos 6.0 Mg 2.4
• 6/24 UA protein gt300 mg/dl, WBC 2-5,RBC packed,
  fine granular casts, RBC casts
• 7/02 Urine protein 2g/day

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Laboratory Data

• HIV negative
• Hep B SAb positive, SAg negative
• Hep C negative
• Syphilis IgG/TPPA positive, RPR negative

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Any ideas?
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• A Diagnostic Test was Performed

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Normal glomerulus
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Nodular mesangial sclerosis
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Crescentic necrotizing GN
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RBC casts
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IgA C3
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(No Transcript)
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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

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IgA nephropathy
Postinfectious GN
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Laboratory Data

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

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Final Diagnosis

• MRSA- post infectious GN

22
Objectives

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

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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

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APIGN Histology
Humps
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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
  201808)
• Literature reports recovery rate in adults
  53-76

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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

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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
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APIGN Presentation

• Endocapillary proliferation 70-100
• Crescents (gt 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

• 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)

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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

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Comorbidities and Histology
With comorbidities
No comorbidities
Moroni G et al, Nephrol Dial Transplant 2002 17
1204
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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
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PIGN of all biopsies
with atypical infection sites
complete remission
with severe interstitial infiltration
Moroni G et al, Nephrol Dial Transplant 2002 17
1204
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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 (p0.116)

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
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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
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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 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
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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
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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

• 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
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(No Transcript)
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Endocapillary proliferation
Nodular sclerosis
Subendothelial and subepithelial deposits
Granular IgA
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IGA-PIGN vs IgA nephropathy
IgA nephropathy ?, IgA1 and J chain
predominance?
Nasr SH et al, Kidney International 2007 71
1317
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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 gtgt predominantly
  mesangial deposition

Nasr SH et al, Kidney International 2007 71
1317
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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
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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

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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

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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

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Thanks!