Dr. Ghadeer Mokhtar Consultant pathologists and nephropathologist, KAU

Dr. Ghadeer Mokhtar Consultant pathologists and nephropathologist, KAU

CLINICAL HISTORY A 4 year old Saudi girl presented to the ER with generalized body swelling, decrease urine output with passing dark color urine, weakness and decrease activity for 7 days. History of sore throat and fever 3 weeks prior and she received antibiotic.

CLINICAL EXAMINATION She was vitally stable apart from high blood pressure. Systemic examination was unremarkable apart from generalized body edema.

LABORATORY FINDINGS Creatinine 551Umol/l (55-115 Umol/l) Urea 20.5 mmol/l (2.5-6.4 mmol/l). Hyperkalemia ( 7.7 mol/l) CBC : Hb is 10.1 Albumin is 17 g/l ( 40.2-47.6) High ESR and C-reactive protein.

LABORATORY FINDINGS Urinalysis: Protein++, Blood +++, RBCs :880. C3 and C4 normal. Hepatitis screen normal. ASO titer: Normal c-anca and p-anca are negative. ANA was weakly positive. High IgA level in blood : 2.29 ( 0.4-2.00)

8 glomeruli, 3 GS, 4 crescents, 1 mesangial cellularity

IgG

IgA

IgM

C3

DIAGNOSIS:

Crescentic GN secondary to IgA nephropathy. 15 glomeruli LM, IF and EM 11/15 glomeruli crescents Oxford classification: M0, S1,E1, T1.

CLINICAL COURSE Admitted to PICU, received antihypertensive medication and started on peritoneal dialysis. After stabilization she undergone u/s guided renal biopsy

CLINICAL COURSE Started on methylprednisolone 400 mg IV OD over 6 hrs. alternating with oral prednisolone 30 mg OD. No immunosuppressive therapy is given as parents refused. Discharged after 7 days and readmitted 2 weeks later for peritonitis for that received antibiotics and discharged.

CLINICAL COURSE Followed in the clinic last seen in December 2013 doing well in medication. Last urinalysis showed 2+ protein with trace blood. Creatinine was 64 umol/l.

HISTORY IgA nephropathy was first described by J. Berger et al. in 1968 The most common glomerulonephritis worldwide. Greatest frequency in Asians and Caucasians, and is relatively rare in blacks.

EPIDEMIOLOGY In native kidney biopsy, IgA nephropathy accounts for : All Biopsies % USA 5 10 Asia 30 40 Europe 15 20 GN Biopsies

CLINICAL FEATURES Present at any age. There is a peak incidence in the second and third decades of life. A male to female 2:1.

CLINICAL FEATURES Most cases of IgA nephropathy are clinically restricted to the kidney. Cirrhosis, celiac disease, inflammatory bowel disease, ankylosing spondylitis and HIV infection are all associated with a high frequency of glomerular IgA deposition. However, most patients have little or no evidence of glomerular disease.

CLINICAL FEATURES 40 to 50 % : one or recurrent episodes of visible hematuria, usually following an upper respiratory infection. 30 to 40 %: microscopic hematuria and usually mild proteinuria, and are incidentally detected on a routine examination 10 %: nephrotic syndrome or acute rapidly progressive glomerulonephritis picture

CLINICAL FEATURES 1/3 clinical remission with resolution of proteinuria and hematuria. 1/3 progressive decline in GFR with ESRD in 20 years. 1/3 benign clinical course with persistent hematuria and proteinuria (< 1g/day)

CLINICAL PROGNOSTIC INDICATORS heavy proteinuria at presentation and/or during follow-up, elevated serum creatinine level at presentation. Hypertension at presentation. (D'Amico G, Semin Nephrol 2004) Weak clinical predictors of a poor prognosis include older age at presentation, male sex, and the absence of a history of recurrent macroscopic hematuria. (D'Amico G. Am J Kidney Dis 2000)

PATHOLOGY It is an immune-complex-mediated glomerulonephritis Glomeruli typically contain generalizeddiffuse granular mesangial deposits of IgA mainly IgA1. less intense IgG, and C3.

PATHOLOGY IgA deposits may also be seen on kidney biopsy in individuals with no evidence of renal disease. The reported incidence of mesangial IgA deposition in apparently healthy individuals ranges from 3 to 16 percent with no evidence of renal disease. (Suzuki K. Kidney Int 2003)

PATHOGENESIS

FOUR HIT THEORY OF IGA NEPHROPATHY 1 st Hit 2 nd Hit 3 rd Hit 4 th hit Increased galactose defiecient IgA1 Production of unique antiglycan antibodies Formation of pathogenic IgA1 containing immune complexes Glomerular injury Mestecky J, Annu Rev Pathol. 2013

PATHOGENESIS Abnormally glycosylated IgA1. Genetically determined. Modified by infections. Antibodies against abnormally glycosylated IgA Excessive IgA1 antibody production in response to mucosal antigen exposure. Increased polymerization/aggregation of IgA1. Reduced clearance of circulation IgA complexes. Increased affinity of mesangial cells for and reaction to underglycosylated IgA1 accumulation

GENETIC FACTORS: Three genome-wide association studies (GWAS) have identified loci associated with IgAN within the major histocompatibility complex. (Feehally J, et al. J Am Soc Nephrol 2010)

GENETIC FACTORS: A GWAS that included 3144 IgA nephropathy patients of Chinese and European ancestry also identified five independently associated loci including a region containing a deletion of CFHR1 and CFHR3 at chromosome 1q32, and a locus at chromosome 22q12. Gharavi AG, et al Nat Genet 2011.

GENETIC FACTORS: A GWAS that included 4137 Chinese patients with IgAN identified loci at 17p13 and 8p23. Yu XQ, et al. Nat Genet 2012.

GENETIC FACTORS: Another significant susceptibility locus that appears to be important in familial forms of IgA nephropathy is on chromosome 6q22-23 Linkage to this locus (called IGAN1) was identified by genome-wide analysis of 30 kindreds from Italy and the United States. Gharavi AG. Nat Genet 2000.

HSP Henoch Schönlein purpura is an immune-mediated vasculitis associated with immunoglobulin A (IgA) deposition predominantly affecting the skin, joints, gastrointestinal tract, and kidneys. Despite the different clinical features, histologic and immunofluorescence findings in Henoch-Schönlein purpura nephritis are indistinguishable from those of IgA nephropathy. The risk of progression to chronic kidney disease in patients with Henoch Schönlein purpura nephritis, ranges from 5 to 20% in children, higher in adults, and is approximately 30%. (Coppo R, et al Am J Kidney Dis 2006)

Mesangioproliferative GN Proliferative GN Chronic GN Crescentic GN End-stage kidney Asymptomatic hematuria /proteinuria Acute nephritic RPGN Chronic nephritis

Several classification schemes. Non has been achieved widespread acceptance. Lack of definitions, use of vague terminology, lack of evidence base and inclusion of both active and chronic lesions in the definition of a single category.

LEE HASS WHO Lupus terminology I-normal by LM I-Focal mesangioproliferative I-Focal mesangioproliferative II. Mesangioproliferaive II- Moderate focal proliferative III-focal proliferative II-focal sclerosing III. Focal proliferative. IIIC. Focal sclerosing III-Mild diffuse proliferative IV-Moderate diffuse proliferative. V-Severe diffuse proliferative IV-Diffuse proliferative IV. Diffuse proliferative V-chronic sclerosing VI. Chronic sclerosing

THE OXFORD CLASSIFICATION 2005, 2006, 2008 Nephrologists and pathologists. 17 centers. Eight countries. Four continents. 265 patients, 206 adults and 59 children. F/U of a minimum of 3 years or ESRD or 50% decline in egfr.

THE OXFORD CLASSIFICATION The goal of oxford classification was to identify specific pathological features that more accurately predict risk of progression of renal disease in IgAN which would enable both clinicians and pathologists to improve the individual patient prognostication.

THE OXFORD CLASSIFICATION Three pathological variables were found to have independent prognostic value : Mesangial hypercellularity. Segmental glomerulosclerosis Tubular atrophy/interstitial fibrosis.

THE OXFORD CLASSIFICATION In addition endocapillary hypercellularity correlated with the response to immunosuppressive therapy.

DEFINITIONS OF PATHOLOGICAL VARIABLES Variable Definition Score Mesangial hypercellularity Segmental glomerulosclerosis < 4 mesangial cells/mesangial area=0 4-5 mesangial cells/mesangial area=1 6-7 mesangial cells/mesangial area=2 >8 mesangial cells/mesangial area=3 The mesangial hypercellularity score is the mean score for all glomeruli Any amount of the tuft involved with sclerosis( but not the whole tuft) or the presence of adhesion. M0 0.5 M1> 0.5 S0-absent S1-present Endocapillary hypercellularity Tubular atrophy/intersitial fibrosis. Hypercellularity due to increased number of the cells within glomerular capillary lumina causing narrowing of the lumina. Precentage of cortical area involved by the tubular atrophy or interstitial fibrosis whichever is greater. E0-absent E1- present T0-0-25% T1-26-50% T2> 50%

VALID FOR BOTH ADULTS AND CHILDREN Retrospective cohort of 59 children and 206 adults. M1 and S1 score were associated with an increased rate of renal function decline. E1 was not. T variable is not assessed as too few children with tubulointersitial disease were present to draw conclusion. (Coppo R, et all. Kidney Int 2010.)

STUDIES VALIDATING THE RESULT OF OXFORD CLASSIFICATION 1. Herzenberg AM, Fogo AB, Reich HN et al. Validation of the Oxford classification of IgA nephropathy. Kidney Int 2011; 80: 310 317. 2. Shi SF, Wang SX, Jiang L et al. Pathologic predictors of renal outcome and therapeutic efficacy in IgA nephropathy: validation of the oxford classification. Clin J Am Soc Nephrol 2011; 6: 2175 2184 3. Katafuchi R, Ninomiya T, Nagata M et al. Validation study of oxford classification of IgA nephropathy: the significance of extracapillary proliferation. Clin J Am Soc Nephrol 2011; 6: 2806 2813. 4. Zeng CH, Le W, Ni Z et al. A multicenter application and evaluation of the oxford classification of IgA nephropathy in adult chinese patients. Am J Kidney Dis 2012; 60: 812 820. 5. Shima Y, Nakanishi K, Hama T et al. Validity of the Oxford classification of IgA nephropathy in children. Pediatr Nephrol 2012; 27: 783 792. 6. Halling SE, Soderberg MP, Berg UB. Predictors of outcome in paediatric ga nephropathy with regard to clinical and histopathological variables (Oxford classification). Nephrol Dial Transplant 2012; 27: 715 722.

STUDIES GENERALLY NOT VALIDATING THE OUTCOME OF OXFORD Five studies found only one of the oxford scores, most often the T score to be independent predictive of the outcome. 1. El Karoui K, Hill GS, Karras A et al. Focal segmental glomerulosclerosis plays a major role in the progression of IgA nephropathy. II. Light microscopic and clinical studies. Kidney Int 2011; 79: 643 654. 2. Kang SH, Choi SR, Park HS et al. The Oxford classification as a predictor of prognosis in patients with IgA nephropathy. Nephrol Dial Transplant 2012; 27: 252 258 3. Lee H, Yi SH, Seo MS et al. Validation of the Oxford classification of IgA nephropathy: a single-center study in Korean adults. Korean J Intern Med 2012; 27: 293 300. 4. Le W, Zeng CH, Liu Z et al. Validation of the Oxford classification of IgA nephropathy for pediatric patients from China. BMC Nephrol 2012;13: 158. 5. Alamartine E, Sauron C, Laurent B et al. The use of the Oxford classification of IgA nephropathy to predict renal survival. Clin J Am Soc Nephrol 2011; 6: 2384 2388.

CRESCENTS? Glomerular crescents were not found to be of prognostic value in the Oxford Classification, due to the low prevalence of crescents in the enrolled cohort by inclusion and exclusion criteria. Crescents have been found to be of prognostic value in some studies. (Shima Y,et al. Pediatr Nephrol 2012.) (Katafuchi R, et al J Am Soc Nephrol 2011) (Walsh M, et al Clin J Am Soc Nephrol 2010)

A recent systematic review of 16 cohorts with 3893 patients found The M, S and T lesion are strongly associated with progression to renal failure independent of all clinical and laboratory parameters. E lesion was not independently associated with renal events, although patients with this lesion were more likely to have received glucocorticoids, potentially obscuring the prognostic significance. Cresents were strongly associated with progression to kidney failure. (Lv J,et al. Am J Kidney Dis. 2013)

IS IT VALID FOR HSP? 61 biopsy-proven patients with Henoch-Schönlein purpura nephritis. Median follow up of 49.3 months. A Kaplan-Meier plot showed that renal event-free survival was significantly longer in patients with <50% crescents than in those with crescents in 50% of glomeruli. Among the components of the Oxford classification, patients with endocapillary hypercellularity (E1) and tubular atrophy/interstitial fibrosis (T1/T2) had lower renal survival rates than those with E0 and T0. In a multivariate Cox model adjusted for clinical and pathologic factors, E1 and T1/T2 were independently associated with reaching a primary outcome, whereas the extent of crescentic lesions was not. ( Ho Kim C, Mod Pathol. 2014 )

CORRELATION WITH IF OR IMMUNOSTAINING FINDINGS The immunohistochemical results from 175 original reports from Oxford Classification cohort were reviewed. Capillary wall IgA and the presence of glomerular IgG deposits were associated with a higher mesangial cellularity score and endocapillary proliferation, but not associated with crescents, glomerulosclerosis, interstitial, or vascular lesions. Capillary wall IgA deposits did not independently predict the clinical outcomes of rate of loss of renal function or renal survival. Poor renal survival was correlated with glomerular IgG deposits with borderline significance. ( Bellur SS, etal. Nephrol Dial Transplant 2011)

ISSUES NEED TO BE ADDRESSED : Does mesangial hypercellularity remain an independent predictor of clinical outcome in patients uniformly treated with RAS blockers? Are there clinical circumstances in which certain histologic lesions (for example, crescents) are predictive of clinical outcome and/or response to immunosuppressive therapy? How reproducible is the association between endocapillary proliferation and therapeutic efficacy? Do lesions not scored in the original Oxford study, such as changes of TMA, have significant prognostic value in amultivariate analysis including clinical and other histologic parameters? (Haas M, et al. Kidney Int. 2013 )

SPECIAL TYPE OF IGA NEPHROPATHY IgA nephropathy with minimal change-like nephrotic syndrome. (Qin J, et al. Clin Nephrol. 2013 ) IgA nephropathy with concurant membranous nephropathy (Stokes MB, Alpers CE. Am J Kidney Dis. 1998 ) IgA nephropathy with concurent ANCA assocaited necrotizing GN (Haas M, et al. Am J Kidney Dis. 2000) (Richer C, et al. Clin Nephrol. 1999 )

IgA dominant acute post staphylococcal infection associated GN. Nasr SH, et al. IgA-dominant acute poststaphylococcal glomerulonephritis complicating diabetic nephropathy. Hum Pathol. 2003 Dec. Worawichawong S, et al. Immunoglobulin A-dominant postinfectious glomerulonephritis: frequent occurrence in nondiabetic patients with Staphylococcus aureus infection. Hum Pathol. 2011 Mandai S, et al. Post-Staphylococcal infection Henoch- Schönlein purpura nephritis: a case report and review of the literature. Ren Fail. 2013

CONCLUSION: IgAN is the most prevalent pattern of glomerular disease in most countries and remains an important cause of ESRD. The exact pathogenesis is still not well-defined but evidence implicate interaction of genetic and environmental factors leading to production of aberrant IgA1. The Oxford Classification is valid classification for prediction of the outcome. Modification of the Oxford Classification is required so that classification can be applied to the patients excluded from the original cohort. Prospective randomized controlled trials are required to elucidate the predictive value of the Oxford Classification. Advances in understanding of the pathogenesis may help with earlier diagnosis and better monitoring of the treatment response and clinical course, and in the development of targeted therapy in the future.