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
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
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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