Prezentace aplikace PowerPoint

1
KIDNEY and GENES Renal manifestation of gene
defects
10th CEEPUS SUMMER SCHOOL, 2007, Zadar, Croatia
"Evaluation of renal function multidisciplinary
approach".
2

• Major functions
• water, electrolyte and acid-base regulation,
• toxin removal,
• secretion of hormones (vitamin D, renin,
  erythropoietin and prostaglandins).

Impairment of the vital functions is the basis
for clinical manifestations of renal diseases.
Renal disorders may be groupedas acquired and
inborn, including inherited.
3
Kidney disorders
. . . . . .
4
Kidney disorders
1 Acquired after
birth 2 Inborn -
prenatally 2.1
Malformations
2.2 Inherited
defects

• 1 Acquired kidney disorders - numerous causes
• ? infections (pyelonephritis,
  glomerulonephritis), ? blockages (obstruction by
  stricture, tumours, stones), ? damage by
  nephrotoxic drugs, toxins, heavy metals.
• 2 Inborn kidney disorders
• 2.1 Malformations of kidney and usually also
  other organs (infection-,drug-, alcohol-, and
  other factors-induced) agenesis, dysplasia,
  stenosis-leading to infection and/or
  destruction of kidney tissue.
• 2.2 Inherited kidney defects with substantial
  genes involvement.

5
2 Inborn 2.2.1
Non-metabolic defects kidney 2.2
Inherited 2.2.2 Non-metabolic - multiple
2.2.1 Non-metabolic defects affecting namely
kidney Polycystic kidney disease Medullary
cystic disease or Juvenile nephronophthisis-uromod
ulin assoc(NPHP1 gene 2q13) Dent's disease,
X-linked nephrolithiasis -CLCN5 gene,
Cl-chann Steroid-resistant cong. nephrotic s.
podocin NPHS2 gene, 1q. 2.2.2 Non-metabolic
defects - parts of multiple malformation
syndromes affecting also other organs, e.g. Lowe
s.- X-linked (oculo-cerebro-renal) -inositol
metabolism, Alport s. - X-linked (hereditary
nephritis with hematuria, hearing loss,
proteinuria, and ophthalmologic
abnormalities), Bartter's and Gitelman's s.-
autosom recess. SLC12A3 gene normotensive
hypokalemic alkalosis with ? calciuria, growth
deficiency, muscle weakness, cramps,
hyperaldosteronism.
6
Polycystic kidney disease
Description Fluid-filled cavities arising from
proximal tubules and collect. ducts acquired
and a hereditary form a commonest inherited
cause of kidney failure. Pathogenesis Two
proteins polycystin-1 (cells extracellular
matrix contacts) and polycystin-2 (ER- bound
cation channel) act in a common pathway, which
controls the width of renal tubules. The loss
of one protein may lead to a disruption of this
pathway and to the uncontrolled expansion of
tubules. Genetics autosomal-dominant (-recess)
form PKD1/PKD2 genes Prevalence 1 500 1 1
000 2.5-15x? (cystic fibr. or sickle cell dis.)
14 x 8 cm/500 g 3.5 kg
7
Symptoms - autosomal dominant form starts by
2nd 4th decade of life flank pain (bleeding
into a cyst) and/or infection, hematuria, high
blood pressure. Cerebral aneurysms, kidney
stones, renal failure. The disease can go
unnoticed. - autosomal recessive f. - starts
early after birth/in the womb. Diagnosis To
check for ultrasound examination patient and
relatives (three or more kidney cysts, cysts in
other organs, and a family history). Treatm
ent No specific therapy is available.
Hypertension, infections and uremia are treated
in conventional manner. nutritious food (growth
hormone), dialysis or transplantation.
tumour bleeding
8
2 Inborn 2.2.1
Non-metabolic defects kidney 2.2
Inherited 2.2.2 Non-metabolic - multiple
2.2.1 Non-metabolic defects affecting namely
kidney Polycystic kidney disease Medullary
cystic disease or Juvenile nephronophthisis-uromod
ulin assoc(NPHP1 gene 2q13) Dent's disease,
X-linked nephrolithiasis -CLCN5 gene,
Cl-chann Steroid-resistant cong. nephrotic s.
podocin NPHS2 gene, 1q. 2.2.2 Non-metabolic
defects - parts of multiple malformation
syndromes affecting also other organs, e.g. Lowe
s.- X-linked (oculo-cerebro-renal) -inositol
metabolism, Alport s. - X-linked (hereditary
nephritis with hematuria, hearing loss,
proteinuria, and ophthalmologic
abnormalities), Bartter's and Gitelman's s.-
autosom recess. SLC12A3 gene normotensive
hypokalemic alkalosis with ?calciuria, growth
deficiency, muscle weakness, cramps,
hyperaldosteronism.
9
Alport syndrome
Description progressive hematuric non-immune
nephritis Pathogenesis defect of collagen
alpha 5(IV) chain ? irregular thickening,
thinning and lamellation in the capillary,
glomerular and epidermal basement membranes.
Genetics X-linked dominant, COL4A5 gene, Xg 22
(also autosomal dominant and -recessive
types) Prevalence 1 5 000 Symptoms
proteinuria, hematuria, platelets defects
hearing loss, leiomyomatosis, hypertension,
ocular defects. Treatment P-bindersvit. D
(osteodystrophy), alkali (acidosis),
erythropoietin (anemia), antihypertensive
therapy transplant.
splintering
10
2 Inborn 2.2.3
Metabolic transport, lithiases 2.2
Inherited 2.2.4 Metabolic others
2.2.5 Various
genetic influence
2.2.3 Metabolic diseases inborn errors of
metabolism, monogenic transport defects
(cystinuria, cystinosis), and urolithiases -
stones formation (hereditary xanthinuria,
-hyperoxaluria, -hyperuricemia cystinuria,
orotic aciduria) 2.2.4 Other inherited metabolic
diseases X-linked-(or autosomal) dominant
hypophosphatemic rickets - defective
Zn-metallo endopeptidase Familial juvenile
hyperuricemic nephropathy Fabry disease is an
X-linked disorder, due to deficiency of
lysosomal ?-galactosidase). 2.2.5 Various renal
diseases with genetic influence,e.g.Inherited
hemolytic-uremic syndrome, or IgA nephropathy.
11
Cystinuria
Description excess of (Cys)2 in urine the
least soluble of all AA crystallizes and forms
stones (calculi) in the kidney, ureter,
bladder (anywhere in the tract). Pathogenesis
transport defect of (Cys)2 Lys, Arg,
Orn Genetics autosomal recessive SLC3A1 AA
transporter gene, chrom. 2p16.3/19q13.1 3
types. Prevalence 1 in 5 7 000 one of the
most common disorder. Symptoms obstruction
urine stagnation infection dilatation
-
parenchym compression,
renal insufficiency pain,
bleeding.
12
Treatment high fluid intake 5 - 7 l per day to
prevent stones formation alkalizing of urine
chelates Penicillamine (Depen, Cuprimine)
forms a complex with Cys that is 50x more
soluble than (Cys)2 itself a side effects.
Percutaneous lithotripsy stones are broken by
ultrawaves, X-ray control. History in
1810 Wollaston found a yellow bladder stone
cystic oxide since it came from the bladder
(Greek kystis bladder).
The cystine stones compared to a quarter (a U.S.
0.25 coin) from the kidney of a young woman by
percutaneous nephrolithotripsy (crushing and
removing the dense stubborn stones characteristic
of cystinuria.
13
(No Transcript)
14
2 Inborn 2.2.3
Metabolic transport, lithiases 2.2
Inherited 2.2.4 Metabolic others
2.2.5 Various
genetic influence
2.2.3 Metabolic diseases inborn errors of
metabolism, monogenic transport defects
(cystinuria, cystinosis), and urolithiases -
stones formation (hereditary xanthinuria,-hyperox
aluria, -hyperuricemia cystinuria, orotic
aciduria) 2.2.4 Other inherited metabolic
diseases X-linked-(or autosomal) dominant
hypophosphatemic rickets - defective
Zn-metallo endopeptidase Familial juvenile
hyperuricemic nephropathy Fabry disease is an
X-linked disorder, due to deficiency of
lysosomal ?-galactosidase)- kidney, heart and
others 2.2.5 Various renal diseases with genetic
influence,e.g.Inherited hemolytic-uremic
syndrome, or IgA nephropathy.
15
Nephropathic cystinosis
Description amino acid (Cys)2 accumulates within
cellular lysosomes of the eye, kidney, thyroid,
brain, reticuloendothel. Pathogenesis transport
defect (cystinosin) leads to buildup of (Cys)2
in various organs and eventual multiple organ
failure. Genetics autosomal recessive CTNS gene
on chrom. 17p13marker D17S829 various CTNS
mutations. Prevalence 1 80 - 100 000
In vivo microscopy/slit-lamp photo of the cornea
with crystals.
16
Cystinosin in the lysosomal membrane. The
N-terminal, containing a signal peptide, resides
inside the lysosome, and the C-terminal, with 1
of 2 targeting motifs, resides in the cytoplasm.
Seven transmembrane regions contain missense,
nonsense, insertion, and deletion mutations
resulting in cystinosis.
17
Symptoms generalized proximal renal tubular
dysfunction, infantile variant is associated
with growth retardation and rickets, ocular
deposits (uvea conjunctiva, cornea, retina),
photophobia, epithelial erosions progressive
renal damage - failure, end-stage renal disease
by 10 ys of age on average.
Electron microscopy of the myocardium cystine
crystal ( 15,000).
Treatment cysteamine reduces storage of
cystine,can retard progression of renal damage if
started early transplantation.
18
? the same patient after transplantation at the
age of 25 ys cushingoid, features, photophobia
with blepharospasm hand - muscle wasting
? 7-year-old boy with short stature and poor
muscular development
? 11-month-old girl with the blond hair and blue
eyes
19
2 Inborn
2.3.1 Kidney cancers 2.3
Multigenetic, -factorial 2.3.2 Diabetes
mellitus 2
2.3.3 Hypertension,
familial
2.3 Multigenic, multifactorial defects The
common type of kidney cancer- clear cellis
caused by a mutation of the Von-Hippel Lindau
(VHL) disease gene, tumor suppressor gene, chrom.
3p) CNS, retina, adrenal gland. VHL protein
forms a complex with other proteins to target the
?-subunit of the HIF- hypoxia - inducible
factor for ubiquitin - mediated degradation of
proteins. Ubiquitin small regulatory
protein used by cells to label old,
damaged, or missfolded proteins for
destruction.www.webtie.org/SOTS/Meetings/Genitour
inary/
2.3.1 Kidney cancers
20
In hypoxia, the complex does not target, and HIF
accumulates. This results in increased
transcription of a number of genes
Von-Hippel Lindau
hypoxia-inducible f,
ubiquitin
vascular endothelial growth f. (VEGF) the
glucose transporter (GLUC-1) or the epidermal
growth factor (EGF) receptor cancerogenesis.
21
2.3.2 Diabetes mellitus type 2
is the leading cause of the end-stage kidney
disease worldwide. The risk of diabetic
nephropathy is partially genetically determined
(18q22.3-q23). A new marker of ? susceptibility
to kidney damage was discovered!A part of the
CNDP1 gene, coding for the carnosinase-1
precursor is associated with nephropathy.
Carnosinase 1 inactivates carnosine, which
protects against the effects of high glucose
levels on renal cells (opposes glycation). Early
carnosine supplement or carnosinase inhibitors
applic.as a therapy for susceptible diabetic
patients!
?-Ala, L-His
a
b
Control (a) and patient (b) with diabetic
nephropathy (more dense staining for
CNDP1). Diabetes. 200554(8)2320-7.
22
2.3.3 Familial hypertension
Recently discovered mutations
in PRKWNK1 and PRKWNK4 genes (which
encode kidney specific WNK1 and WNK4 kinases) are
involved in the regulation of renal Na transport
and its hormonal control are regarded as modifier
genes defining vulnerability to the primary
defect.
Trends Endocrinol Metab 200516(3)98-103.
23
Genes in renal diseases - new findings
Already known gene encoding tubular prostasin,
NX-17 kidney - specific membrane protein, the
chloride channel CLCNKA genes actinin ?4 and
osteonectin, expressed in the glomerulus and
involved in glomerulonephropathies. Novel
(supposed) candidategene ficolin 3 (Hakata
antigen), autoantigen in systemic lupus
erythematosus, expressed only in the liver and
lung now also in kidney! Unexpected renal
expression of detoxification genes in the renal
cortex, bile metabolism genes in the papillary
tips, genes involved in intestinal mucosal
defense in the medulla.
1) kidney plays a role (thought exclusive domain
of other organs ?) 2) other functions of these
genes in the kidney than in other organs?
24
Greetings
from Hradec Králové