Nephrology Rounds
Riki Buchwald, ID fellow
December 17th 2008
Case

46 y old AA man with h/o GSW to right trochanter in 8/07, s/p
ORIF at OSH
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Admitted to Bellevue 9/07; found to have wound infection/OM
with polyresistant Pseudomonas
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Extensive debridement performed but hardware left in place
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Underwent long-term treatment with polymyxin from 10/07
on. Course complicated by renal failure in 11/07 that resolved
with polymyxin dose adjustment.
Case
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Hardware removed on 3/12/08
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Wound cx with MRSA
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Received 4 week course of vancomycin and 6 week course
of polymyxin after hardware removal; course completed at
the end of April
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
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
Physical Exam
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BP 150/89 HR 93 T 97.2 97% RA
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Ext: b/l 3+ LE edema
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
Laboratory Data
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Wbc 11.4, 73% PMN,18% Lymph, Eos WNL
Hgb 7.8
Plt 332
Hepatic: 42/64/201/0.2/8.2/3.4
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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
Creatinine
BUN
6/17
1.1
11
6/21
1.5
18
6/30
2.7
36
7/06
3.9
47
7/18
6.8
59
7/30
8.9
64
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7/30: K: 5.2, Ca: 8.8, Phos: 6.0 Mg: 2.4
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6/24: UA: protein >300 mg/dl, WBC 2-5,RBC packed, fine granular casts, RBC casts
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7/02: Urine protein: 2g/day
Laboratory Data
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HIV: negative
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Hep B: SAb positive, SAg negative
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Hep C: negative
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Syphilis: IgG/TPPA positive, RPR negative
Any ideas?
A Diagnostic Test was Performed
Normal glomerulus
Nodular mesangial sclerosis
Crescentic necrotizing GN
RBC casts
IgA
C3
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
IgA nephropathy
Postinfectious GN
Laboratory Data
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C3: 172( 75-140); C4 28.5 (10-34)
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Urine immunofixation: negative
ASLO: 57
ANA, ds DNA, ANCA: negative
Anti-GBM: negative
Final Diagnosis
MRSA- post infectious GN
Objectives
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Postinfectious Glomerulonephritis (PIGN)
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Current trends in PIGN in adults
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Staphylococcus and IgA dominant PIGN
Postinfectious Glomerulonephritis
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Acute postinfectious GN (APIGN) = disease of childhood
Commonly following a streptococcal infection (= APSGN)
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Clinical presentation:
3 phase sequence: infection - interval - nephritic syndrome
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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
APIGN: Histology
Humps
APIGN: Outcome
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Long term follow up studies: excellent prognosis for most
children with the epidemic form
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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)
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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)
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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)
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Literature reports recovery rate in adults 53-76%
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
APIGN in Adults
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% of all renal biopsies: 0.6% - 4.6%
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Median age 49 - 58 yrs
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Underlying disease: 40-50%
- Alcoholism +/- cirrhosis 2 - 57%
- Diabetes 8 - 29%
- COPD 7 - 33%
- IVDU 3 - 27%
- Malignancy 5 - 10%
No
comorbidities
+ comorbidities
Moroni G et al 2002
APIGN: Presentation
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Nephritic syndrome: 60%
Nephrotic Syndrome: 30-50%
Mean serum creatinine:
1.5-6.4 mg/dl
(with comorbidities/crescentic GN)
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Mean 24 hr-protein:
3.6 g (with comorbidities)
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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%
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EM:
Mesangial deposits: 33 - 90%
Subendothelial: 44 - 75%
Humps: 94 - 100%
Sites of Infection and Microbiology
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URI: 24-44%
SSTI: 5-25%
Lung: 16-18%
Endocarditis: 1-13%
Dental: 0-13%
UTI: 1-12%
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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)
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8% of patients simultaneous
diagnosis (20% of pt with
endocarditis and 27% with
PNA)
Comorbidities and Histology
With comorbidities
No comorbidities
Moroni G et al, Nephrol Dial Transplant 2002; 17: 1204
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
% PIGN of all biopsies
% with “atypical” infection sites
% with severe interstitial infiltration
Moroni G et al, Nephrol Dial Transplant 2002; 17: 1204
% complete remission
Do Steroids Matter ?
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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
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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)
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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)
Montseny JJ et al, Medicine 1995; 74: 63
Nasr SH et al, Medicine 2008; 87: 21
Moroni G et al, Nephrol Dial Transplant 2002; 17: 1204
Staph and the Kidney
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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
MRSA and PIGN
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In 1980, Spector et al first reported 3 pt with S. aureus visceral
abscesses who developed acute mesangial proliferative GN with
mesangial IgA deposits
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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
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Elevated serum IgA/IgG and immune complexes levels
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High number of T cells with Vb+ usage in the TCR: ? Superantigen
driven event
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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
MRSA and PIGN
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Recent reports: similar features after MSSA and MRSE infections
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Clinical presentation:
- acute RF with hematuria, severe proteinuria
- onset 2-16 weeks after infection
- +/- purpura, +/- hypocomplementemia
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Mostly mesangial proliferative GN, often with crescents and (pre-)
dominant mesangial IgA deposits
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Several cases do not have subepithelial humps, the “hallmark” of PIGN
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Treatment of infection lead to resolution of GN; however 40-60% of pt
developed ESRD
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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
Pathogenesis
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Link between staphylococcal enterotoxins and T cell/cytokine
activation?
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Superantigen triggered cytokine activation leads to class switching
to IgA?
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Link to a staphylococcal cell wall antigen that co-localizes in
glomeruli of patients with MRSA nephritis?
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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
Diabetes, Staph and the Kidney
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In 2003, Nasr et al in New York reported 5 pt with DM who developed
an IgA dominant GN after staphylococcal infection
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Histology showed diabetic nephropathy with superimposed
endocapillary proliferation with neutrophils and some degree of
interstitial inflammation
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IgA sole immunoglobulin in 3 cases; IF with mesangial or
mesangial/capillary granular IgA and C3 staining
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EM: all cases with predominantly mesangial deposits and sparse
subepithelial deposits
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Findings were similar to IgA nephropathy but all pt had low
complement, endocapillary hypercellularity and humps
Nasr et al, Hum Pathol 2003; 34: 1235
Endocapillary proliferation
Granular IgA
Nodular sclerosis
Subendothelial and
subepithelial deposits
IGA-PIGN vs IgA nephropathy
IgA nephropathy:
, IgA1 and J chain predominance?
Nasr SH et al, Kidney International 2007; 71: 1317
Diabetes and IgA nephropathy
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Increased serum levels of IgA and IgA immune complexes
- secondary to (silent) mucosal infection
- abnormal IgA clearance (abnormal glycosylation or sialylation)
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Thickened BM and mesangial sclerosis hinders subepithelial deposit
formation >> predominantly mesangial deposition
Nasr SH et al, Kidney International 2007; 71: 1317
IgA predominant postinfectious GN
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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
Case follow-up
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7/11: Proximal femoral osteotomy and acetabular excavation performed;
antibiotic cement beads with vancomycin/tobramycin placed
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On 7/17, vancomycin switched to linezolid given worsening renal failure
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Creatinine slowly improved:
7/30 8.9
8/14 5.9
10/08 2.7
Summary
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Epidemiology of APIGN is shifting
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Diabetes, alcoholism and age emerge as major risk factor; prognosis is
worse in pt with comorbidities and renal inflammation
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Microbiology is changing and staphylococci are increasingly important
in APIGN
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Histologic pattern are changing, especially in immunocompromised
persons
Summary
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IgA predominant APIGN is recognized as 3rd entity of
staphylococcal associated GN
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IgA dominant PIGN can be associated with diabetic
nephropathy
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Exact pathologic diagnosis and pathogenesis is still under
debate
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This entity has to be differentiated from IgA nephropathy (and
pauci-immune ANCA related GN)
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Treatment of infection can lead to recovery; however, pt with
underlying diabetic GS have poor prognosis