21 st Budapest Nephrology School
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1 Genetics of non-diabetic kidney disease 21 st Budapest Nephrology School Barry I. Freedman, MD, FACP John H. Felts III Professor (Internal Medicine) Chief, Section on Nephrology
2 Podocyte disorders β3 integrin cell anchor β3 integrin cell anchor
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5 Major etiologies of FSGS Idiopathic. until genes are discovered Hereditary Infection: HIV, Parvo B19, Hep C, CMV, EBV Medication/toxin: pamidronate, heroin, interferon-therapy, Li 2+, calcineurin inhibitor toxicity Hyperfiltration: obesity, reflux, nephron loss, aging Hypertension-attributed: focal global GS with interstitial & vascular changes in those of African ancestry Sickle cell nephropathy Role of SuPAR
6 Treatment of FSGS/SRNS Steroids, calcineurin inhibitors, cytotoxic agents Is there a role for MMF or Rituximab? Plasmapharesis if recurs after kidney txp (>30%) Idiopathic forms: Best Prognosis: tip lesion (origin prox tubule) Worst Prognosis: collapsing variant Do causative genes impact diagnosis & therapy?
7 Mutations in FSGS Dependent on: Family history Single generation favors autosomal recessive * first affected child will appear to be sporadic, suspect AR if consanguineous parents Multi-generation favors autosomal dominant Incomplete penetrance (genetic carriers not manifesting disease) can lead to failure to detect AR or AD inheritance Age at onset Ethnicity Histology
8 XXX APOL1 apolipoprotein L1 AR glomerulosclerosis in those with African ancestry NPHS2, TRPC6: and other genetically-mediated forms of FSGS: poor response to immuno-suppression low recurrence after txp Rood, Deegens & Wetzels. NDT 2012; 27:1-9
9 Prevalence of FSGS/SRNS mutations in childhood Congenital nephrotic syndrome (CNS) Detectable mutations approach 100% of cases In Finland 95% relate to nephrin NPHS1 In non-finnish other gene variants found Infants (4-12 months) and early childhood (1-5 years) SRNS - podocin (NPHS2) mutations common (up to 40% of familial and 17% sporadic SRNS in this group) WT1 up to 16% of children consider in females (or males with abnormal genital development)
10 Adult familial FSGS Typically autosomal dominant (except APOL1) Penetrance may be incomplete with non-nephrotic proteinuria 1. Formin gene INF2 - up to 17% of cases 2. Transient receptor potential cation channel subfamily 6 TRPC6 up to 12% 3. Αlpha-actinin-4 ACTN4 up to 3.5% 4. Apolipoprotein L1 APOL1 (AR) 70% of FSGS & HIVassociated collapsing FSGS, >50% hypertensionattributed nephropathy in African Americans
11 Podocin NPHS2 in adult FSGS Rare in cases of adult sporadic FSGS Exception = compound heterozygosity for mutations in the common R229Q polymorphism + one pathogenic NPHS2 variant in Western Europe (Machuca E; KI 2009; 75: ) R229Q in 5-10% of Caucasians R229Q in 1-2.5% of African Americans R229Q alone non-pathologic NS age ~19 yrs in R229Q compound hets Far lower disease freq. outside of Western Europe
12 Clinical Correlates Recessive mutations in NPHS2, CD2AP, & PLCE1 more often associated with severe disease presenting with early onset proteinuria/esrd in infancy and childhood Dominant mutations in ACTN4, TRPC6, & INF2 more often associated with later onset proteinuria in 2 nd decade and ESRD in 3 rd -4 th decades APOL1 accounts for 70% of idiopathic FSGS and HIVAN in African Americans; >50% of hypertension-attributed CKD and ESRD lesion can be focal global glomerulosclerosis NPHS2 accounts for 40% of childhood familial FSGS and 6-17% of sporadic childhood FSGS INF2 accounts for 17% of adult onset familial FSGS Remaining mutations are rare in adult sporadic FSGS (do not screen for them)!
13 Genetic causes of syndromal SRNS/FSGS (Rood, Deegens & Wetzels. NDT 2012; 27:1-9) * Relatively more common Gene Product Pattern Associated conditions Comments WT-1 WT-1* AD Denysh-Drash: male pseudohermaphroditism, CA (Wilms ), nephrosis (DMS) mos to 3-4 yrs Frasier: male pseudohermaphroditism, FSGS, gonadoblastoma, 2-6 yo, ESRD <30 yrs Childhood presentation: Mutations in phenotypic females (may be XY) or males with genital abn (cryptorchism, hypospadius, testicular atrophy) Isolated FSGS in adulthood Mitochondrial trna leucine 1 trna LEU(UUR) maternal MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis & stroke-like episodes). Also: diabetes, deafness, visual impairment, cardiomyopathy May present with isolated FSGS, typically in adulthood LAMB2 Laminin β2 AR Pierson s syn (microcoria and other complex ocular disorders, nephrotic syndrome with diffuse mesangial sclerosis ITGB4 CD151 B4-integrin Tetraspanin AR AR Epidermolysis bullosa Epidermolysis bullosa, sensorineural deafness, nail dystrophy Typical age at onset < 1 year Only 1 case w/ biopsy: GBM thickening/fragmentation (not FSGS) SCARB LMX1b Non-muscle myosin IIA SCARB2/ LIMP-2 LIM Hbox TF1* AR AD Action myoclonus-renal failure syn (progressive myoclonic epilepsy + CKD) Nail-patella syn (hypoplastic/absent patella, finger and toenail dysplasia, elbow dysplasia, glaucoma is common MYH9* AD Epstein, Sebastian, & Fechtner syndromes Macrothrombocytopenia with progressive sensorineural deafness Renal abnormalities occur - typically microalbuminuria, FSGS with overt proteinuria is rare
14 Genetic screening in clinical practice Will results influence: treatment of your patient? screening for extra-renal disease? family counseling? decisions on kidney transplantation?
15 Family counseling Gene detection in childhood SRNS is high. This can help parents with family planning Pre-natal genetic testing is possible If a sibling of a patient with a known mutation develops NS? less benefit to steroids Family planning for patients homozygous or compound het. NPHS2 mutations + partner with R229Q variant (10% Western Europeans) = 50% disease risk, possibly more severe Women with isolated WT1 (FSGS) = potential for Denysh-Drash Syndrome or Frasier Syndrome in children
16 Potential drawbacks of genetic testing Expense Evaluation of genes one at a time Selected populations often studied, where other (more common) genetic etiologies have been excluded can inflate prevalence rates Few studies test for heterozygous mutations in two different genes
17 Family planning in adult onset FSGS If strong family history suggests AD disease (note possible incomplete penetrance) risk of transmission is high and should be discussed Sporadic FSGS without a family history prevalence of mutations is very low There is less value in screening adult sporadic FSGS; except for possible NPHS2 R229Q compound hets. w/ one NPHS2 pathogenic mutation. Half of offspring will have the pathogenic NPHS2 variant w/o disease; but if combined with R229Q it will cause disease. Hence, consider testing for R229Q as up to 10% of population may carry it.
18 Clinical Screening All children with congenital nephrotic syndrome Children with familial and sporadic SRNS Adults with familial FSGS Limited value in adults with sporadic FSGS, except testing young adults for the R229Q NPHS2 variant
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21 Genetic screening and kidney transplantation Recurrence after transplantation is lower in familial forms of FSGS Detection of homozygous or compound heterozygous risk mutations predict lower risk of recurrence Living donors may be more likely to donate knowing recurrence rates are low Assist with living related donor selection in familial FSGS (exclude donors with risk variants) Exceptions Congenital Nephrotic Syndrome due to NPHS1: recurrence rate ~25% and possibly related to antibodies against nephrin Anti-GBM disease in Alport s Syndrome
22 55 year old African American female with hypertensive ESKD. End-stage kidney disease is often listed in the medical record without mention of an underlying cause or as due to hypertension with little documentation
23 Case Presentation 45 year old African American female referred for serum creatinine umol/l (1.7 mg/dl), egfr 42 ml/min/1.73 m 2 PMH: Hypertension diagnosed at age 39 Serum Cr 70.7 umol/l (0.8 mg/dl) age 21; none since Married, school teacher, no ETOH/IVDA/smoking Family Hx: ESKD maternal aunt (CGN); brother (HIVAN) PE: BP 162/96; exam otherwise unremarkable Lab: U/A negative blood or protein; urine protein:creatinine ratio 350 mg/g; Hemoglobin A1c normal; HIV negative Renal ultrasound: increased cortical echogenicity; kidney length: 10.0 cm L and 10.5 cm R Diagnosis: hypertensive (arteriolar) nephrosclerosis? Correct Diagnosis: APOL1-associated nephropathy
24 Familial clustering of ESKD in African Americans Etiology ESKD Cases Non-Nephropathy Controls Hypertension 40.0% T2 Diabetes 37.0% SLE 28.0% HIV 24.4% 8.5% 7.0% 0.0% 6.0% Freedman et al. AJKD 93, 95, 97, 99
25 Freedman BI et al AJKD: 21; , 1993
26 Hypertensive (arteriolar) nephrosclerosis is a vascular lesion egfr can stabilize with lowering of BP & lipids; smoking cessation
27 Focal global glomerulosclerosis in AASK was mis-attributed to hypertension African American Study of Kidney Disease and Hypertension egfr ml/min; Uprot < 2.5 gm/day, hypertension, no diabetes
28 APOL1-associated disease: b) thyroidization-type TA e) disappearing pattern GS f) solidified pattern GS Larsen CP, Freedman BI Mod Pathol 2014
29 Cumulative Incidence (%) 60 Cumulative Incidence of Events in (1) ACEI with Low BP Group and (2) Non-ACEI with Usual BP Groups Only Trial Mixed Trial and Cohort Only Cohort Non-ACEI w/ Usual BP ACEI with Low BP Follow-Up Time (Years) Appel LJ et al. Arch Intern Med 2008
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31 Tsetse fly Glossina Genus Chancre Human African Trypanosomiasis Trypanosoma brucei rhodesiense
32 Association of trypanolytic apol1 variants with kidney disease in African Americans Giulio Genovese*, David J. Friedman*, Michael D. Ross, Laurence Lecordier, Pierrick Uzureau, Barry I. Freedman, Donald W. Bowden, Carl D. Langefeld, Taras K. Oleksyk, Andrea L. Uscinski Knob, Andrea J. Bernhardy, Pamela J. Hicks, George W. Nelson, Benoit Vanhollebeke, Cheryl A. Winkler, Jeffrey B. Kopp, Etienne Pays, Martin R. Pollak Science 329: , 2010 XXXXX Autosomal recessive inheritance
33 photo from
34 Spectrum of APOL1-associated nephropathy Focal Global Glomerulosclerosis Hypertensive nephropathy Focal Segmental Glomerulosclerosis Collapsing FSGS (HIVAN) Odds Ratio=7.3 OR=17 OR=29 Proteinuria & nephropathy progression rate Freedman, Bowden & Rich. Brenner and Rector s The Kidney 9 th Edition Severe lupus nephritis - Sickle cell nephropathy
35 APOL1 - strongest genetic association in any complex disease Risk variant frequencies: ~13% of African Americans possess two risk variants and 39% one risk variant Population attributable risk: 70% in FSGS and 70% in HIVAN Odds Ratio: 29 HIVAN, 17 FSGS, 7.3 H-ESKD, 2.8 Lupus-ESKD Variation in APOL1 fully explains: a) excess rates of non-diabetic ESKD in African Americans relative to European Americans b) poorer allograft survival in transplanted kidneys from deceased donors with recent African ancestry c) much of the poorer outcome in lupus nephritis in African Americans, compared to European Americans Risk variants virtually absent in Europeans/Asians/Hispanics Far weaker association seen with mild nephropathy (reduced egfr or low level albuminuria) in the general population
36 Antinuclear Antibodies (SLE - lupus nephritis) Progression of Hemoglobin SS (Sickle cell nephropathy) Nephropathy Two APOL1 risk variants Focal Global Glomerulosclerosis (FGGS) Why doesn t hyperglycemia trigger diabetic glomerulosclerosis?
37 APOL1 clinical implications Two coding variants in APOL1 fully explain the excess risk of non-diabetic nephropathy in African Americans vs. European ancestry populations Associated with earlier age at ESRD Weak association with mild CKD/proteinuria, strong with ESRD Progression factor in FSGS, FGGS or hypertension-attributed nephropathy, sickle cell nephropathy, lupus-associated ESRD APOL1 genotype of kidney donors explains shorter graft survival from African-ancestry donor kidneys Kidney disease and progression in AASK participants strongly associate with APOL1 genotype an effect independent from blood pressure treatment target or medication class used
38 Survival of kidneys donated by African Americans Reeves-Daniel & Freedman AJT 2011
39 Modulators of APOL1 nephropathy APOL1 Genetic Susceptibility: (recessive) 12% African Americans NPHS2, SDCCAG8, BMP4 APOL1 gene gene interactions APOL1 gene environment interactions (HIV infection) polyoma viruses? antinuclear antibodies chronic kidney disease often with secondary hypertension collapsing FSGS sickle cell nephropathy FSGS lupus nephritis- ESRD focal global glomerulosclerosis Proposed pathogenesis of APOL1 associated nephropathy Freedman, Bowden & Rich. Brenner and Rector s The Kidney 2011
40 Modifying Factors CJASN 2014
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