Nephrology Rounds

Riki Buchwald, ID fellowDecember 17th 2008

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.

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

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

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

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

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

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

Laboratory Data HIV: negative

Hep B: SAb positive, SAg negative

Hep C: negative

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

C3: 172( 75-140); C4 28.5 (10-34)

ASLO: 57

ANA, ds DNA, ANCA: negative

Anti-GBM: negative

Urine immunofixation: negative

Final Diagnosis

MRSA- post infectious GN

Objectives

Postinfectious Glomerulonephritis (PIGN)

Current trends in PIGN in adults

Staphylococcus and IgA dominant PIGN

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 diuresis4 weeks: normalization of creatinine3-6 months: resolution of hematuria; resolution of mesangial hypercellularityYears: resolution of proteinuria

APIGN: Histology

Humps

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%

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 % 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

Nocomorbidities

+ comorbidities

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%

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%

Comorbidities and HistologyNo comorbidities

With 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

% complete remission% with severe interstitial infiltration

% with “atypical” infection sites

Moroni G et al, Nephrol Dial Transplant 2002; 17: 1204

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 steroidsIndications: renal insufficiency with/without crescentsCR in 12/17 patients with steroid therapy and 10/23 without (p=0.116)

Nasr SH et al, Medicine 2008; 87: 21Moroni G et al, Nephrol Dial Transplant 2002; 17: 1204Montseny JJ et al, Medicine 1995; 74: 63

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

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: 256Koyama A et al, Kidney Internat 1995; 47: 207

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: 297Yoh K et al, Nephrol Dial Transplant 2000; 15: 1170Shimizu Y et al, J Nephrol 2005; 18: 249Okuyama S, Clin Nephrol 2008; 70: 344

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: 297Yoh K et al, Nephrol Dial Transplant 2000; 15: 1170Shimizu Y et al, J Nephrol 2005; 18: 249

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

Endocapillary proliferation

Subendothelial and subepithelial deposits

Granular IgA

Nodular sclerosis

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

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

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

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

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

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