Case # 2 Christopher Larsen, MD Arkana Laboratories Disclosure of Relevant Financial Relationships USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Larsen has nothing to disclose. Clinical history 12-year-old African American male with nephrotic-range proteinuria (5 g by urine protein to creatinine ratio). Presents to clinical attention after the finding of hypertension on physical exam for school sports. Patient denies rash, joint pain, abdominal pain, SOB Past medical history: ADHD Clinical history Medications- none Family history- Paternal uncle on dialysis and multiple family members with hypertension Physical examination: - T: 97.1, P: 73, BP: 152/95 - slightly obese(bmi 26.4) otherwise unremarkable without edema or rash Laboratory findings Serum creatinine of 0.6 mg/dl Serum albumin 3.3 g/dl Weakly positive ANA antibody (1:40) ANCA, dsdna, Smith negative C3/C4 normal 1
IgG 2
Diagnosis Kidney, Biopsy: Focal Segmental Glomerulosclerosis, see Comment Comment: The most common etiology of FSGS in young African Americans is APOL1-associated nephropathy. APOL1 genotyping would be required for definitive diagnosis. The differential diagnosis would include FSGS due to a primary podocytopathy as well as secondary FSGS. Immunofluorescence and electron microscopy also identify mesangial immune deposits. The significance of this mild mesangial deposition is undetermined. Possible etiologies would include autoimmune-related and infection-associated deposition. Final Diagnosis Kidney, Biopsy: Focal Segmental Glomerulosclerosis, see Comment G1 G2 Comment: APOL1 genotyping has been performed and shows that the patient is homozygous for APOL1 risk alleles. Therefore, the findings in the biopsy are consistent with APOL1-associated nephropathy. Background Prevalence and histopathologic spectrum in renal biopsies Etiology African Americans and Renal Disease Fourfold increased risk for end-stage kidney disease (ESKD) Admixture mapping-chromosome 22 Nat Genet. 2008 October; 40(10): 1175 1184. 3
Risk variants - C-terminal domain of APOL1 G1- two missense variants (S342G and I384M; African American allele frequency 0.23) G2-6 bp in-frame deletion (N388del:Y389del; African American allele frequency 0.13) J Am Soc Nephrol. 2011 Nov;22(11):2129-37. Science. 2010 Aug 13;329(5993):841-5. Science. 2010 Aug 13;329(5993):841-5. J Clin Invest. 2011 Sep;121(9):3367-74. FSGS (OR=17) HIVAN (OR=29) Hypertension-attributed ESKD (OR=7) ESRD in SLE (OR=2.6) Collapsing Glomerulopathy in SLE (OR=5.4) Other FSGS (OR=17) HIVAN (OR=29) Hypertension-attributed ESKD (OR=7) ESRD in SLE (OR=2.6) Collapsing Glomerulopathy in SLE (OR=5.4) Other Enrollment: Children and adults with primary steroid-resistant 2-40 years of age Biopsy-proven FSGS >egfr 40 ml/min per 1.73 m 2 urine protein-to-creatinine ratio >1 g/g 94 subjects genotyped for APOL1 renal risk variants Two APOL1 risk alleles -African American: 23/32 (72%) -European American, non-hispanic: 2/42 (7%) -European American, Hispanic: 2/17 (12%) J Am Soc Nephrol. 2015 Jun;26(6):1443-8. J Am Soc Nephrol. 2015 Jun;26(6):1443-8. 4
FSGS histologic variant 0 or 1 APOL1 risk allele 2 APOL1 risk alleles Collapsing 3 (4%) 8 (30%) Tip 10 (15%) 2 (7%) Cellular 2 (3%) 0 Perihilar 7 10%) 2 (7%) NOS 45 (67%) 15 (56%) J Am Soc Nephrol. 2015 Jun;26(6):1443-8. J Am Soc Nephrol. 2015 Jun;26(6):1443-8. FSGS (OR=17) HIVAN (OR=29) Hypertension-attributed ESKD (OR=7) ESRD in SLE (OR=2.6) Collapsing Glomerulopathy in SLE (OR=5.4) Other J Am Soc Nephrol. 2015 Jun;26(6):1443-8. Are there morphologic differences between hypertensive nephrosclerosis and APOL1-associated nephropathy? Inclusion Self-reported African Americans with a clinical diagnosis of CKD stage 3 Renal biopsy with diagnosis of arterionephrosclerosis History of hypertension and progressive renal failure Nonspecific chronic injury changes on kidney biopsy including arteriosclerosis. Exclusion Nephrotic syndrome History of diabetes mellitus or any systemic diseases associated with CKD except for systemic hypertension. 5
196 biopsies from AA with arterionephrosclerosis Phenotype: Type and number of glomerulosclerosis Mesangial changes GBM duplication Glomerulomegaly GBM thickening Degree of foot process effacement Degree of interstitial fibrosis Degree and type of tubular atrophy Microcystic tubular dilatation Interstitial inflammation Degree of arterial intimal fibrosis Degree of arteriolar hyalinosis Genotype for APOL1 risk alleles Which morphologic findings show correlation with the presence of 2 APOL1 risk alleles? Morphologic lesions significantly associated with two APOL1 risk variants (2 vs 0/1) Solidified and disappearing glomerulosclerosis Thyroidization-type tubular atrophy Microcystic tubular dilatation Histopathologic criteria <50% globally sclerotic glomeruli of the obsolescent type At least 1 focus of microcystic tubular dilatation >50% of total tubular atrophy of thyroidization type The presence of at least two criteria had a sensitivity of 43% and a specificity of 92% for presence of two APOL1 risk variants. Interobserver agreement among the renal pathologists was good for identifying cases with two risk variants (at least two of these histologic criteria) with a k of 0.71. 6
FSGS (OR=17) HIVAN (OR=29) Hypertension-attributed ESKD (OR=7) ESRD in SLE (OR=2.6) Collapsing Glomerulopathy in SLE (OR=5.4) Other APOL1 risk alleles strongly impact the risk of ESRD in African Americans with lupus nephritis, as well as the time to progression to ESRD. Arthritis Rheumatol. 2014 Feb;66(2):390-6. 546 biopsies from AA with lupus nephritis Phenotype: ISN/RPS Collapsing lesions MCTD Activity and chronicity scores TMA Arteriosclerosis Genotype for APOL1 risk alleles Which morphologic findings show correlation with the presence of 2 APOL1 risk alleles? J Am Soc Nephrol. 2013 Apr;24(5):722-5. J Am Soc Nephrol. 2013 Apr;24(5):722-5. APOL1 risk allele status 0 risk alleles, n=188 (34%) 1 risk allele, n=264 (48%) 2 risk alleles, n=94 (17%) CG ----------------------------ISN/RPS Classification---------------------------- Mesangial (1 or 2) Proliferative (3 or 4) Membranous (Class 5 only) Class 3 or 4 and 5 Sclerosing (Class 6) 1 (0.5%) 10 (5%) 79 (42%) 48 (26%) 50 (27%) 1 (0.5%) 12 (5%) 26 (10%) 89 (34%) 77 (29%) 65 (25%) 6 (2%) 13 (14%) 11 (12%) 40 (43%) 20 (21%) 21 (22%) 2 (2%) APOL1 risk allele status 0 risk alleles, n=188 1 risk allele, n=264 2 risk alleles, n=94 Global Glom. # (%) 105 (56%) 156 (59%) 53 (56%) FSGS, NOS # (%) 84 (45%) 114 (43%) 52 (55%) Total Crescents cases # (%) 67 (36%) 84 (32%) 42 (45%) Nonnecrotizing crescents # (%) 35 (19%) 53 (20%) 30 (32%) TMA MCTD Mean Mean # (%) # (%) activity chronicity score score 13 20 (11%) 4.3 2.9 (7%) 11 (4%) 33 3.6 3.4 (13%) 8 24 4.2 3.9 (9%) (26%) OR=5.4 (P<0.001, Odds ratio CI 95 =2.4 12.1) P=0.008 P=0.001 J Am Soc Nephrol. 2013 Apr;24(5):722-5. J Am Soc Nephrol. 2013 Apr;24(5):722-5. 7
FSGS (OR=17) HIVAN (OR=29) Hypertension-attributed ESKD (OR=7) ESRD in SLE (OR=2.6) Collapsing Glomerulopathy in SLE (OR=5.4) Other 120 biopsies from AA with PLA2Rassociated MG Phenotype: ISN/RPS Collapsing lesions MCTD Activity and chronicity scores TMA Arteriosclerosis Genotype for APOL1 risk alleles Which morphologic findings show correlation with the presence of 2 APOL1 risk alleles? 8
Biopsy findings known to be associated with homozygosity for APOL1 risk alleles HIVAN FSGS in AA Lupus nephritis with collapsing lesions Collapsing Glomerulopathy in SLE Arterionephrosclerosis in AA Membranous with collapsing lesions Etiology? Lack of nephropathy in patients with null mutations Overexpression of APOL1 is harmful to cells and expression of APOL1 risk variants is more injurious than wild-type PLoS One. 2012;7(12):e51546. Kidney Int. 2015 Feb;87(2):332-42 Proc Natl Acad Sci U S A. 2016 Jan 26;113(4):830-7. Proc Natl Acad Sci U S A. 2016 Jan 26;113(4):830-7. Summary Overexpression of APOL1 G1 and G2 risk alleles led to impaired mitochondrial function compared to G0 This preceded intracellular potassium depletion Common cause of African American kidney disease Morphologic changes are relatively nonspecific Precise molecular pathogenesis remains unknown J Am Soc Nephrol. 2016 Nov 7. [Epub ahead of print] 9
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