Precision Medicine in Kidney Diseases

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Ivemark syndrome. Short rib-polydactyly syndromes (Jeune syndrome/asphyxiating thoracic ... Split-hand/split-foot malformation (SHFM). Townes-Brocks ...
NEVEEN A SOLIMAN Professor of Pediatrics Kasr Al Ainy School of Medicine Cairo University [email protected]

Precision Medicine in Kidney Diseases

Puzzling terminology!

Best solution Precise therapies

Every patient

Treatments targeted to the needs of individual patients on the basis of more advanced diagnostics and phenotypic characteristics that distinguish a given patient from other patients with similar clinical presentations

Ability to examine patient’s genetic profile

Kasr Al Ainy Faculty of Medicine

Cairo University

Improve clinical outcomes for individual patients

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Kasr Al Ainy Faculty of Medicine

Cairo University

“Precision medicine refers to the tailoring of medical treatment to the individual characteristics of each patient. It does not literally mean the creation of drugs or medical devices that are unique to a patient, but rather the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment.”

Committee of the U.S. National Research Center

Kasr Al Ainy Faculty of Medicine

Cairo University

1990

The Human Genome Project (HGP) goal:  determining the sequence of nucleotide base pairs that make up human DNA (Homo Sapiens)  identifying and mapping all of the genes of the human genome

2003

Kasr Al Ainy Faculty of Medicine

Cairo University

22,300 protein-coding genes

Kasr Al Ainy Faculty of Medicine

3.3 billion base pairs

Cairo University

pubmed - precision medicine 8000 7000 6000 5000

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Kasr Al Ainy Faculty of Medicine

1960

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Cairo University

Kasr Al Ainy Faculty of Medicine

Cairo University

 At least 150 different disorders  An overall prevalence of about 60–80 cases per 100 000 in Europe and the US Africa & ME???

 At least 10% of adults and nearly 70% of children who progress to renal-replacement therapy have an inherited kidney disease Kasr Al Ainy Faculty of Medicine

Cairo University

Inherited Kidney Diseases 70% of Pediatric end stage kidney disease

Kasr Al Ainy Faculty of Medicine

10% of Adult end stage kidney disease

Cairo University

Global total consanguinity rates Hammamy et al, Genetics in Medicine 2011

CKD THE MENDELIAN SURPRISE

Kasr Al Ainy Faculty of Medicine

Cairo University

INHERITED KIDNEY DISEASES

Structural

Functional

Kasr Al Ainy Faculty of Medicine

• Ciliopathies • CAKUT • • • •

Inherited glomerulopathies Inherited tubulopathies Metabolic disorders & Inherited nephrolithiasis

Cairo University

I. Genetic disorders of renal growth and structure

CILIOPATHIES ADPKD, type 1 & 2 ARPKD Nephronophthisis types 1–11 Medullary cystic kidney disease Joubert syndrome related disorders (JSRD) Meckel-Gruber syndrome (MKS) Bardet-Biedl syndrome types 1–12 Alström syndrome Sensenbrenner syndrome (Cranioectodermal dysplasia) Oral–facial–digital syndrome 1 (OFD1) Ivemark syndrome Short rib-polydactyly syndromes (Jeune syndrome/asphyxiating thoracic dystrophy) Ellis-van Creveld syndrome (EVC)

CONGENTIAL ABNOR-MALITIES OF THE KIDNEY AND URINARY TRACT (CAKUT) Renal agenesis Renal hypoplasoia/dysplasia syndrome Multicystic renal dysplasia Vesicoureteral reflux Branchio-oto-renal syndrome (BOR) Fraser syndrome HDR syndrome Kallman syndrome Renal coloboma syndrome Renal cysts and diabetes syndrome (RCAD), GCKD Split-hand/split-foot malformation (SHFM) Townes-Brocks syndrome

II. Genetic disorders of renal Function

GLOMERULAR DISEASES Congenital SRNS (Finnish type) SRNS type 2,3 & 4 Pierson syndrome SRNS, adult-onset Denys-Drash syndrome, Frasier syndrome Nail-Patella syndrome Mitochondrial disorders with SRNS Lysosomal disorders with SRNS Alport syndrome (XL, AR, AD) Alport syndrom with leiomyomatosis Schimke immuno-osseous dystrophy

RENAL TUBULAR DISEASES AND METABOLIC DISEASES Renal glucosuria Aminoacidurias Proximal renal tubular acidosis (pRTA) Hypophosphatemic rickets Cystinosis Lowe syndrome Bartter syndrome types 1–4 Gitelman syndrome Liddle syndrome Gordon syndrome Pseudohypoaldosteronism type 1 & 2 SeSAME syndrome Distal renal tubular acidosis (dRTA) Diabetes insipidus, nephrogenic Fabry disease Familial amyloidosis

NEPHROLITHIASIS - Cystinuria - Dent disease - Lysinuric protein intolerance - Primary hyperoxaluria type 1,2 & 3 - Adenine-phosphoribosyl-transferase deficiency - Xanthinuria - Distal renal tubular acidosis

Soliman, Nephron Clinical Practice, 2012

Deep clinical phenotyping Imaging

Pathology

Kasr Al Ainy Faculty of Medicine

Clinical

Laboratory

Cairo University

Steroid Resistant Nephrotic Syndrome (SRNS)

Kasr Al Ainy Faculty of Medicine

Cairo University

Kasr Al Ainy Faculty of Medicine

Cairo University

Glomerular Filtration Barrier

Kasr Al Ainy Faculty of Medicine

Cairo University

Genetic mutations causing NS

Preston et al., Pediatr Nephrol 2019

Kasr Al Ainy Faculty of Medicine

Cairo University

• 71% Hereditary • 8 years Podocytopathies

ESRD • 29% Non-hereditary • 8 years SRNS

Prof. Neveen A Soliman

Kasr Al Ainy Faculty of Medicine

Cairo University

Nephrotic syndrome (NS) Conventional diagnoses using a combination of clinical presentation and descriptive biopsy information do not accurately predict risk for progression

NS in the first year of life

Congenital

Childhood

Adulthood

Infantile

Genetic mutation Kasr Al Ainy Faculty of Medicine

Cairo University

Accessible Technology

Preston et al., Pediatr Nephrol 2019

Prof. Neveen A Soliman

Kasr Al Ainy Faculty of Medicine

Cairo University

Prof. Neveen A Soliman

Kasr Al Ainy Faculty of Medicine

Cairo University

Sadowski et al, JASN 2015

Prof. Neveen A Soliman

Kasr Al Ainy Faculty of Medicine

Cairo University

Prof. Neveen A Soliman

Kasr Al Ainy Faculty of Medicine

Cairo University

Renal Survival by Nephrotic Syndrome Steroid Responsiveness Disease Category

Kasr Al Ainy Faculty of Medicine

Cairo University

Is Nephrology Keeping Pace with Genetic and Genomic Discoveries?

Kasr Al Ainy Faculty of Medicine

Cairo University

Genetically “solved” and unsolved cases of ESRD

Kasr Al Ainy Faculty of Medicine

Cairo University

Clinical Implications Early and accurate diagnosis hereditary monogenic kidney diseases is important for:

Therapeutic intervention

Appropriate treatment • Prognosis • Genetic counseling • Transplantation strategy •

Genetic counselling

Transplantation strategy

Prof. Neveen A Soliman

Kasr Al Ainy Faculty of Medicine

Cairo University

Precision medicine

Case scenarios Case 1 • Two-years-old male child with steroid resistant nephrotic syndrome (SRNS) • Kidney biopsy: focal segmental glomerulosclerosis (FSGS) • Exome sequencing confirms the diagnosis of hereditary podocytopathy with mutation in COQ6 gene • Treatment: COQ10 supplementation Prof. Neveen A Soliman

Kasr Al Ainy Faculty of Medicine

Cairo University

Case scenarios Case 2 • Eleven-months-old female infant with polyuria, dehydration, FTT and hypophosphatemic rickets “renal Fanconi syndrome” • Slit lamp examination: No deposits • Mutational analysis of CTNS gene confirms the diagnosis of nephropathic cystinosis • Treatment: Cysteamine bitartarate therapy

Prof. Neveen A Soliman

Kasr Al Ainy Faculty of Medicine

Cairo University

Case scenarios Case 3 • Seven-years-old female child with end stage kidney disease • Kidney USS: hyperechogenic kidneys - Atrophic!! • Mutational analysis of AGXT gene confirms the diagnosis of primary hyperoxaluria type 1 • Treatment: AVOID isolated kidney transplantation  RECURRENCE Combined liver & kidney Tx Prof. Neveen A Soliman

Kasr Al Ainy Faculty of Medicine

Cairo University

Prof. Neveen A Soliman

Kasr Al Ainy Faculty of Medicine

Cairo University

Kasr Al Ainy Faculty of Medicine

Cairo University

Kasr Al Ainy Faculty of Medicine

Cairo University

Genomics is moving into the mainstream

Kasr Al Ainy Faculty of Medicine

Cairo University

Preston et al., Pediatr Nephrol 2019

Kasr Al Ainy Faculty of Medicine

Cairo University

There is a growing momentum to improve personalized patient management

Kasr Al Ainy Faculty of Medicine

Cairo University

Kasr Al Ainy Faculty of Medicine

Cairo University

Las Meninas