Post infectious glomerulonephritis, PIGN

Post Infectious Glomerulonephritis

October’15 Nephrology topic reviewSathienwit Rowsathien, Flt. Lt., MD.

Background

• PIGN is an immune mediated glomerulonephritis.– Cause by many type of non renal infection.– Most common is PSGN. • PSGN 28-47% (decline from the past).• Staphylococcus12-24%• Gram negative bacteria 22%

Chapter 9; Infection-related GN. Kidney International Supplements (2012) 2, 200–208; doi:10.1038/kisup.2012.22

Burden of disease

• Overall, rates are higher in children than adults.– PSGN primarily affected children (2-12 yrs)

• Only 10% in adult (>40 yrs)

• Currently, no large scale published study of infection associated GN other than streptococcus.

Epidemiology

• Global estimated of PSGN is around 472,000/yrs– 96.6% from less developed countries.– Represent only the clinical case, asymptomatic case is

predicted to be 4-19 times greater.• Incidence decline in the past decade due to – Better health care, wide spread of ABO used.

Jackson, S.J., et.al, Systematic Review: Estimation of global burden of non-suppurative sequelae of URI: rheumatic fever and PSGN. Trop Med Int Health, 2011. 16(1): p. 2-11.


Samih H. Nasr, et.al, Bacterial infection-related GN in adults. Kidney international, 2013. 83: p. 792-803.

Pathogenesis

• Pathognomonic is the deposition of immune complex in GBM, especially in PSGN (GAS).– Nephritogenic antigens lead to the activation of

complement pathway. • Many of Nephritogenic GAS strain, especially Streptococcal factor (M

Protein); type 1,2,3,4,12,25,49 (Skin) or 2,47,49,55,57,60 (throat).• Nephritis associated plasmin receptor (NAPlr), co-localized with C3.

– Increase permeability of GBM.– Deposition of immune complexs.• C3 pathway tissue destruction, IgG deposition.

Nordstrand, A., et.al, Pathogenic Mechanism of APSGN. Scandinavian J Infect Dis, 1999. 31(6): p. 523-537.

Rodriguez-Iturbe, B. and J.M. Musser, The current state of PSGN. J Am Soc Nephrol, 2008. 19(10): p. 1855-64.


Pathological appearance

• Base on the glomerular change…– Proliferation of mesangial, endothelial and epithelial cells,

inflammatory exudate and early deposition of C3 then IgG.• Immune deposition classified into 3 patterns. – Starry Sky pattern.– Garland pattern.– Mesangial pattern.

Sorger, K., et al., Subtypes of APIGN. Synopsis of clinical and pathological features. Clin Nephrol, 1982. 17(3): p. 114-28.

M Nagata. PIGN and variants. Division of kidney and vascular pathology, graduate school of human sciences, University of Tsukuba, Japan.




Clinical presentation• Abrupt onset of Acute nephritis(1)

– 1-3 wks after streptococcal throat infection– 3-6 wks after skin infection

• Typical Presentation(2)

– Hematuria, gross or microscopic (100%)– Low complement (C3) (90%)– Edema (75-90%)– Proteinuria (80-92%)– Hypertension (60-80%)– Oliguria (10-58%)– Other such as facial puffiness, malaise, weakness or anorexia.

(1) Nordstrand, A., et.al, Pathogenic Mechanism of APSGN. Scandinavian J Infect Dis, 1999. 31(6): p. 523-537.(2) Sotsiou F. Postinfectious glomerulonephritis. Nephrol Dial Transplant 2001;16 Suppl 6:68-70.


Basic investigation

• Urinalysis reveal hematuria in all patients.– Proteiuria may be subnephrotic or nephrotic range.

• Serum creatinine may elevated.• Renal ultrasound may not required.– Imaging is usually use for screening structural abnormalities.

Specific Investigation• Antibody to streptococcus.

– Antistreptolysin O titer (ASO) following throat infections. (90% sensitivity)

– Anti-DNAse B titers following skin infections. (80% sensitivity)

– Other such as Anti-hyaluronidase (AHase), Anti-streptokinase (ASKase), Anti-nicotinamide- adenine-dinucleotidase (Anti-NAD)

• Culture evidence of streptococcus (10-70%).• Complement level.

– Decrease of C3 and CH50. – Normal or slightly low of C4.

Blyth CC, et.al. PSGN in Sydney: a 16-year retrospective review. J Paediatr Child Health 2007;43:446-50.

Management

• Mainstay of treatment is supportive.– Close monitoring BP, renal function and clinical.– Volume overload Diuresis and restrict sodium.– Antihypertensive as need.

• Treat underlying infection.– Penicillin for persist streptococcal infection.

• Erythromycin if patient is allergic to Penicillin.

G Singh. PIGN. An update on Glomerulopathies – Clinical and treatment aspect ,2011:113-124.

Management

• Complete recovery is 90% of children and 60% of adult.– The rest developed hypertension or renal failure.

• Recheck serum complement at 6-8 wks.• Annually check BP, renal function test and urinalysis

every 1-3 month for 1 yr then yearly.• Kidney biopsy not indicated in all patient.

G Singh. PIGN. An update on Glomerulopathies – Clinical and treatment aspect ,2011:113-124.

Management

• Pulse of IV Methylprednisolone may consider in extensive glomerular crescent/ RPGN.– Currently no evidence from RCT.

• Adult patient who have persistent proteinuria >1gm/ day should receive ACE-I or ARBs.


Recovery phase

• Mostly urinary abnormalities clear within 12 wks.– Proteinuria may persist from 6 months – 3 yrs.– Hematuria may persists from 1-4 yrs.

• C3 level usually normalize within 8-12 wks.

Yoshizawa, N., Acute glomerulonephritis. Intern Med, 2000. 39(9): p. 687-94.

Kidney Biopsy

• Indicated in..– Persistent of low C3 beyond 6-12 wks.– Persistent or rapid declined of renal function.– Persistent HTN or lack of renal improvement within 2 wks.– Recurrent Hematuria.– Cannot excluded other diagnosis…

• Absent history of latent period.• Normal complement level.• Negative anti streptococcal antibodies.• Symptom and sign of other systemic disease such as Malar rash.

Prognosis

• Extremely variable may fully recovery or progressive.– Children usually have excellent prognosis.

• Unfortunately, 25% of Adult will progress to CRF.– Epidemic spreading may have better prognosis, except

S. Equi Zooepidermicus.(1)

– Lack of a clinical or biomarker for predict outcome.• Neutrophil gelatinase-associated lipocalin (NGAL-AKI), not yet

evaluated in PIGN(2)

(1) Sesso, R. and S.W. Pinto, Five-year follow-up of patients with epidemic GN dueto Streptococcus zooepidemicus. Nephrol Dial Transplant, 2005. 20(9): p. 1808-12.

(2) Haase, M., et al., Accuracy of NGAL in diagnosis and prognosis in AKI: a systematic review and meta-analysis. Am J Kidney Dis, 2009. 54(6): p. 1012-24.

Prognosis• Poor prognosis indicated in…(1)

– History of childhood PSGN.(2)

– Older age.– History of massive proteinuria.– History of Alcoholism or drug abused.– Underlying disease such as Diabetes, Cardiovascular and liver disease.– Persistent abnormal renal function.– History of dialysis at presentation.

• Biopsy feature(including crescent) or steroid treatment not correlated with prognosis of Adult PIGN(3)

(1) Rodriguez-Iturbe, B. and J.M. Musser, The current state of PSGN. J Am Soc Nephrol, 2008. 19(10): p. 1855-64.(2) White, A.V., et.al. Childhood PSGN as a risk factor for chronic renal disease in later life. Med J Aust, 2001. 174(10): 492-6.(3) Nasr SH,et al. APIGN in the modern era: experience with 86 adults and review of the literature. Medicine (Baltimore) 2008; 87: 21–32.

Prevention• Evidence base using Benzathine Penicillin G IM for halted

bacterial transmission in GAS skin infection.(1)

• In experimental, Nephritic process is prevented if penicillin is given within 3 days of strep- infection.(2)

• Prevention of epidemic PSGN required community level control of skin sores, infected scabies by regular washing.

• GAS vaccine currently under development.(3)

(1) Johnston, F., et al., Evaluating the use of penicillin to control outbreaks of APIGN. Pediatr Infect Dis J, 1999. 18(4): p. 327-32.(2) Bergholm, A.M. and S.E. Holm, Effect of early penicillin treatment on the development of experimental PSGN. Acta Pathol

Microbiol Immunol Scand C, 1983. 91(4): p. 271-81.(3) Georgousakis, M.M., et al., Moving forward: a mucosal vaccine against GAS. Expert Rev Vaccines, 2009. 8(6): p. 747-60.

Sample Variant of PIGN

• Staphylococcus associated GN.– Associated with ventrilovascular shunt, IE .– Some resemble IgA nephropathy.

• HBV associated GN.• HIV associated GN such as HIVAN, Immunotactoid.• Report case of other infection associated GN.

GN associated with IE

• Incidence range from 22-78%.– Highest among IV drug abused.

• Most typical finding is focal and segmental proliferative GN.

• Prognosis is good, despite ABO as IE (4-6 wks).

Shunt nephritis related GN

• Immune mediated complex GN.– Complication of chronic infection via ventriculovascular

shunts, common in treatment of hydrocephalus.(1)

• In contrast to vascular shunt, VP shunt rarely developed GN.

• Typical type I MPGN (dense deposit mesangial and subendothelial).

• Typical organisms are Staphylococcus spp.

Iwata Y, Ohta S, Kawai K et al. Shunt nephritis with positive titers forANCA specific for proteinase 3. Am J Kidney Dis 2004; 43: e11–e16.

HCV infection related GN

• HCV frequently causes extrahepatic manifestation.• Kidney involvement…

– Most common associated with type II cryoglobulinemia.(1)

• Type I MPGN (Cryoglobulin deposits).

• Best long term prognostic indicator is HCV with SVR.– RNA clearance from serum at least 6 month.

• Paucity of controlled study in HCV associated GN.– Rituximab plus Peg-interferon a2b and Ribavarin show good response

in stabilized kidney function in cryoglobulinemic vasculitis.(2)

(1) Chapter 9; Infection-related GN. Kidney International Supplements (2012) 2, 200–208; doi:10.1038/kisup.2012.22(2) Saadoun D, Resche-Rigon M, Sene D et al. Rituximab combined with Peg-interferon-ribavirin in

refractory HCV -cryoglobulinaemia vasculitis. Ann Rheum Dis 2008; 67: 1431–1436.

HBV infection related GN• Pattern of kidney involvement included.

– MN is the most common form, especially in children.– Other such as MPGN, FSGS and IgAN.

• Exclude other cause of GN first.• Prognosis…

– In children high spontaneous remission.– In adult usually progressive, especially with abnormal LFT and

nephrotic syndrome, >50% progressing to ESRD.• Treat HBV infection.• Currently no data about efficacy of treatment in HBV- related GN.


HIV related GN

• Variety spectrum of kidney disease.• HIVAN is the most common cause of CKD in HIV-1.– APOL1 gene related.– Typical collapsing FSGS on pathology.– HAART is beneficial in both preservation and improvement

in kidney function.• Unfortunately, it may not effective in other GN associated with

HIV infection.

• ACE-I may benefit in HIV with nephrotic syndrome.


Schistosomal nephropathy• S.Mansoni and S.japonicum, blood fluke.

– Incidence is not well defined.• GN most commonly seen in young adult males.• Commonly seen eosinophiluria (65%) and

hypergammaglobilinemia (30%).• Aware co-infection with salmonella. Especially in Hepatosplenic

involvement.• Once established GN, currently no effective therapy.

– None of immunosuppresant recommended.• Prevent by Praziquantel or Oxamiquine.

Filarial nephropathy• Loa loa, Onchocerca volvulus, W. bancrofti and B. Malayi.

– Immune mediated from worm antigens.• Urinary abnormalities have been reported 11-25%.• Nephrotic syndrome 3-5%, concomitant with polyarthritis and

chorioretinitis. Especially in lymphatic filariasis.• Can induce diffuse GN and MPGN, MPGN, MND or Sclerosing GN.• Treat by Ivermectin or Diethylcarbamazepine.• Proteinuria can increase and kidney function may worsen

following initiation of therapy due to immune process.


Malarial nephropathy

• P.Falciparum.– May resulted in AKI or proliferative GN.

• P.Malariae.– Variety of kidney disease especially MN or MPGN.

• Currently no RCT for evidence base treatment.– Suggestion only appropriate anti-Malarial agent.


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Post infectious glomerulonephritis, PIGN