Genetics diseases in

urinary tract

objectives
Understand several genetics diseases in kidneys
Cystic Kidney Disease
Polycystic Kidney disease (autosom dominant, autosome
recessive)
medulla cystic disease
MeckelGruber Syndrome
Nephronophthisis
Dent's disease
Alport syndrome
Potter syndrome

Gen

Genes are segments of DNA, the long molecules that

reside in each of a persons cells. Genomes are total
gen in the cell
Genes : race, inheritance; the smallest unit of
genetic material, coded by DNA; DNA spiral strain
(double helix) compose chromosome
The genes, through complex processes, build
proteins for growth and maintenance of the body.
Dogma gene expression: DNA RNA - protein
At conception, DNAor genesfrom both parents
are passed to the child.
Genetics constitution: genotype; its expression :
phenotype (in many stages: biochemistry;
physiology, histology, anatomy, psychology)

Genetic diseases
A genetic disease occurs when one or both
parents pass abnormal genes to a child at
conception.
Abnormal genes caused by mutation
genetic disease: genopathic disease (gene
mutation) and chromosomal diseases
Genopathy: malformative (embryonic
stage); tissue stage, molecular stage
Mutant gene : single effect or multiple
(pleiotrophic: sindromology)

Autosomal dominant& recessive,

x-linkage
If receiving an abnormal gene from
just one parent is enough to produce
a disease in the child, the disease is
said to have dominant inheritance.
If receiving abnormal genes from
both parents is needed to produce
disease in the child, the disease is
said to be recessive.

 A genetic disease can also occur through a

spontaneous mutation.
The chance of acquiring a dominant disease is
higher than the chance of acquiring a recessive
disease.
A child who receives only one gene copy for a
recessive disease at conception will not
develop the genetic diseasesuch as
autosomal recessive Polycystic Kidney Disease
but could pass the gene to the following
generation

Autosomal recessive
pattern inheritance

MeckelGruber
Syndrome MIM 249000
(ciliopathy)
mitotic spindle
(note: first;1:
dominant
2: recessive;3:
recessive x linkage
Nephronophthisis MIM
256100 (ciliopathy)
Signaling
Autosomal recessive
PKD
Gitelman syndrome

Autosomal dominant PKD

polycystic kidn
ey disease
MIM173900
Papillorenal
syndrome
Medullary
cystic kidney
disease
(ciliopathy
receptor)

dominant
disorders are
caused by
mutations in
genes on the
X chromosome

Dent's
disease
Alport
syndrome

Polycystic kidney disease

(PKD)
polycystic kidney syndrome
is a genetic disorder characterized by the growth of
numerous cysts in the kidneys.
When cysts form in the kidneys, they are filled with
fluid.
PKD cysts can profoundly enlarge the kidneys while
replacing much of the normal structure, resulting in
reduced kidney function and leading to kidney
failure.
In the United States, about 600,000 1 people have
PKD, and cystic disease is the fourth leading cause of
kidney failure.

Two major inherited forms of PKD

exist:
Autosomal dominant PKD is the most
common inherited form. Symptoms
usually develop between the ages of 30
and 40, but they can begin earlier, even in
childhood. About 90 percent of all PKD
cases are autosomal dominant PKD.
Autosomal recessive PKD is a rare
inherited form. Symptoms of autosomal
recessive PKD begin in the earliest months
of life, even in the womb

 The cysts grow out of nephrons, the tiny

filtering units inside the kidneys.
The cysts eventually separate from the
nephrons and continue to enlarge. The kidneys
enlarge along with the cystswhich can
number in the thousandswhile roughly
retaining their kidney shape.
In fully developed autosomal dominant PKD, a
cyst-filled kidney can weigh as much as 20 to
30 pounds. High blood pressure is common and
develops in most patients by age 20 or 30.

Autosomal dominant PKD

is the most common inherited disorder of the kidneys.
The phrase autosomal dominant means that if one
parent has the disease, there is a 50 percent chance
that the disease gene will pass to a child. In some cases
perhaps 10 percentautosomal dominant PKD occurs
spontaneously in patients. In these cases, neither of the
parents carries a copy of the disease gene.
Many people with autosomal dominant PKD live for
several decades without developing symptoms. For this
reason, autosomal dominant PKD is often called adult
polycystic kidney disease. Yet, in some cases, cysts
may form earlier in life and grow quickly, causing
symptoms in childhood.

autosomal dominant PKD

ADPKD (or "Adult-onset PKD") is much more common
but less severe than autosomal
recessive polycystic kidney . In 85% of patients, ADPKD
is caused by mutations in the gene PKD1 on
chromosome 16 (TRPP1); in 15% of patients mutations
in PKD2 (TRPP2) are causative. A third locus PKD3 is the
cause of a very small percentage of cases.
Polycystic kidney disease is the most common lifethreatening genetic disease, affecting approximately 7
million people worldwide. Autosomal dominant
polycystic kidney disease affects up to 1 in 1000 people,
while the autosomal recessive type is estimated to
occur in approximately 1 in 20,000 people. [1][2]

Autosomal dominant
ADPKD is a late-onset disorder characterized by
progressive cyst development and bilaterally
enlarged kidneys with multiple cysts.
It is a genetic disorder resulting from mutations in
either the PKD-1 or PKD-2 gene. Cyst formation
begins in utero from any point along the nephron,
although fewer than 5% of nephrons are thought
to be involved.
As the cysts accumulate fluid, they enlarge,
separate entirely from the nephron, compress the
neighboring renal parenchyma, and progressively
compromise renal function.

The most common

symptoms
are pain in the back and the sidesbetween the ribs and hips
and headaches. The pain can be temporary or persistent,
mild or severe.
People with autosomal dominant PKD also can experience the
following complications:
urinary tract infectionsspecifically, in the kidney cysts
hematuriablood in the urine
liver and pancreatic cysts
abnormal heart valves
high blood pressure
kidney stones
aneurysmsbulges in the walls of blood vesselsin the brain
diverticulosissmall pouches bulge outward through the colon

 In most cases of autosomal dominant PKD,

patients have no symptoms and their
physical condition appears normal for many
years, so the disease can go unnoticed.
Physical checkups and blood and urine tests
may not lead to early diagnosis.
Because of the slow, undetected
progression of cyst growth, some people
live for many years without knowing they
have autosomal dominant PKD.

Autosomal dominant PKD

is usually diagnosed
by kidney imaging studies
The most common form of diagnostic
kidney imaging is ultrasound, but
more precise studies, such as
computerized tomography (CT) scans
or magnetic resonance imaging (MRI)
are also widely used.

USG (ultrasonography)

-Machine
-Sound
-Echo
-Density
(solidity)
-Operator
-MRI

How is autosomal dominant PKD treated?

Although a cure for autosomal dominant PKD is
not available, treatment can ease symptoms
and prolong life.
When PKD causes kidneys to failwhich
usually happens after many yearsthe patient
requires dialysis or kidney transplantation.
About one-half of people with the most
common type of PKD progress to kidney
failure, also called end-stage renal disease
(ESRD).

Autosomal recessive PKD

is caused by a mutation in the autosomal recessive PKD gene,
called PKHD1. The recessive form of polycystic kidney, called
ARPKD (autosomal recessive polycystic kidney disease) is less
common than autosomal dominant polycystic kidney .
Mutations in the PKHD1 (chromosomal locus 6p12.2) cause ARPKD
Other genes for the disease might exist but have not yet been
discovered by scientists.
We all carry two copies of every gene. Parents who do not have PKD
can have a child with the disease if both parents carry one copy of
the abnormal gene and both pass that gene copy to their baby.
The chance of the child having autosomal recessive PKD when both
parents carry the abnormal gene is 25 percent. If only one parent
carries the abnormal gene, the baby cannot get autosomal
recessive PKD but could ultimately pass the abnormal gene to his or
her children.

The signs & symptoms

of autosomal recessive PKD frequently begin before birth,
so it is often called infantile PKD.
Children born with autosomal recessive PKD often, but not
always, develop kidney failure before reaching adulthood.
Severity of the disease varies. Babies with the worst cases
die hours or days after birth due to respiratory difficulties
or respiratory failure.
Some people with autosomal recessive PKD do not develop
symptoms until later in childhood or even adulthood.
Liver scarring occurs in all patients with autosomal
recessive PKD and tends to become more of a medical
concern with increasing age.

Children with autosomal recessive

PKD
experience high blood pressure, urinary tract
infections, and frequent urination.
The disease usually affects the liver and spleen,
resulting in low blood cell counts, varicose veins,
and hemorrhoids.
Because kidney function is crucial for early
physical development, children with autosomal
recessive PKD and decreased kidney function are
usually smaller than average size.
Recent studies suggest that growth problems may
be a primary feature of autosomal recessive PKD

autosomal recessive PKD

diagnosed &treated?
Ultrasound imaging of the fetus or newborn reveals enlarged
kidneys with an abnormal appearance, but large cysts such as
those in autosomal dominant PKD are rarely seen.
Because autosomal recessive PKD tends to scar the liver,
ultrasound imaging of the liver also aids in diagnosis.
Medicines can control high blood pressure in autosomal recessive
PKD, and antibiotics can control urinary tract infections.
Eating increased amounts of nutritious food improves growth in
children with autosomal recessive PKD.
In some cases, growth hormones are used. In response to kidney
failure, autosomal recessive PKD patients must receive dialysis or
transplantation.
If serious liver disease develops, some people can undergo
combined liver and kidney transplantation.

Medullary sponge kidney

(MSK)
is a birth defect of the tubulestiny tubes inside the kidneys.
In a normal kidney, urine flows through these tubules as it is
being formed. In MSK, tiny sacs called cysts form in the medulla
the inner part of the kidneycreating a sponge-like appearance.
The cysts keep urine from flowing freely through the tubules.
MSK is present at birth but most cases do not appear to be
inherited.
Problems caused by MSK include hematuria, or blood in urine;
kidney stones; and urinary tract infections (UTIs). But these
problems do not usually appear until the ages of 30 to 40. MSK
affects about 1 person per 5,000 to 20,000 people in the United
States.1 Researchers have reported that up to 20 percent of
people who form kidney stones have MSK.2 MSK rarely

Medullary cystic kidney disease

medullary sponge kidney
Medullary cystic kidney disease has an autosomal dominant pattern
of inheritance.
MCKD1 has been associated with chromosome 1, but not a specific
gene yet.[1]
MCKD2 has been associated with UMOD on chromosome 16.[2

Also known as Cacchi Ricci disease, medullary sponge kidney is a
congenital disorder of the kidneys characterized by cystic dilatation
of the collecting tubules in one or both kidneys. It has been
estimated to occur with a frequency of 1 in every 5,000 individuals
in a population[citation needed]. The disease is bilateral in 70% of cases.
Individuals with medullary sponge kidney are at increased risk for
nephrolithiasis (kidney stones) and urinary tract infection .
Medullary sponge kidney is frequently discovered incidentally on
IVP (intravenous pyelogram).

symptoms.
For many people, MSK causes no symptoms.
The first sign that a person has MSK is usually
a UTI or kidney stone. UTIs and kidney stones
share many of the same symptoms:
burning or painful urination
pain in the back, lower abdomen, or groin
cloudy, dark, or bloody urine
foul-smelling urine
fever and chills
vomiting

To confirm the diagnosis,

A doctor may suspect MSK when a person
has repeated UTIs or kidney stones.
an x ray called an intravenous pyelogram
(IVP). In an IVP, dye is injected into a vein.
The dye travels through the blood to the
kidneys. As the dye is filtered into the
urinary tract, it makes urine visible on the
x ray and shows any blockage in the
urinary tract. Cysts show up as clusters of
light in an IVP.

In an
intravenous
pyelogram of a
medullary
sponge kidney,
cysts appear as
clusters of
light.

management
No treatment can get rid of cysts in the affected kidneys. Once a doctor is
sure that a person has MSK, treatment focuses on curing existing
infection, removing any stones, and preventing future infection and stone
formation.
UTIs. To treat UTIs, the doctor may prescribe a medicine called an
antibiotic that kills bacteria. A person with MSK may need to continue
taking a low-dose antibiotic to prevent recurrent infections.
Kidney stones. Stone removal may require a procedure called lithotripsy,
which uses sound waves to break stones into sand-like particles. The
particles can then pass easily through the urinary tract with the flow of
urine.
Another way to remove stones is to insert a thin tube called a
ureteroscope through the urethra and bladder to catch the stone and
retrieve it. A person with MSK may be able to prevent more stones from
forming through diet changes or taking medicine. Increasing fluid intake so
the person makes more urine is also very important to reduce the risk of
new stone formation.

Nephronophthisis
is a genetic disorder of the kidneys which affects
children.
It is classified as a medullary cystic kidney disease.
The disorder is inherited in an autosomal recessive
fashion and, although rare, is the most common
genetic cause of childhood kidney failure.
It is a form of ciliopathy. A ciliopathy is a
genetic disorder of the cellular cilia or the cilia
anchoring structures, the basal bodies,[or of ciliary
function

cilia

Signs & Symptoms

Infantile, juvenile, and adolescent forms of nephronophthisis
have been identified.
Although the range of characterizations is broad, patients
typically present with polyuria (production of large volume of
urine), polydipsia (excessive liquid intake), and mild
proteinuria (the abnormal appearance of protein in the
urine), and after several months to years,
end-stage kidney disease, a condition necessitating either
dialysis or a kidney transplant in order to survive.
Approximately 10% of individuals with nephronophthisis also
have so-called "extra-renal symptoms" which can include
blindness, liver problems, severe global developmental delay
or mental retardation, and neurologic involvement in which
the cerebellum is affected.

MeckelGruber
Syndrome,
Meckel syndrome (also known as Gruber
Syndrome, Dysencephalia
Splanchnocystica) is a rare, lethal,
ciliopathic, genetic disorder, characterized by
renal cystic dysplasia, central nervous system
malformations, polydactyly, hepatic
developmental defects, and pulmonary
hypoplasia due to oligohydramnios.
Meckel-Gruber syndrome is named for
Johann Meckel and Georg Gruber

 While not precisely known, it is estimated

that the general rate of incidence,
according to Bergsma,[7] for Meckel
syndrome is 0.02 per 10,000 births.
According to another study done six years
later, the incidence rate could vary from
0.07 to 0.7 per 10,000 births.[8]
This syndrome is a
Finnish heritage disease. Its frequency is
much higher in Finland, where the
incidence is as high as 1.1 per 10,000
births. It is estimated that Meckel
syndrome accounts for 5% of all

Dysplastic kidneys
are prevalent in 95% to 100% of all identified cases. When
this occurs, microscopic cysts develop within the kidney and
slowly destroy it, causing it to enlarge to 10 to 20 times its
original size. The level of amniotic fluid within the womb may
be significantly altered or remain normal, and a normal level
of fluid should not be criteria for exclusion of diagnosis.
Occipital encephalocele is present in 60% to 80% of all
cases, and post-axial polydactyly is present in 55% to 75% of
the total number of identified cases. Bowing or shortening of
the limbs are also common.
Finding at least two of the three features of the classical
triad, in the presence of normal karyotype, makes the
diagnosis solid. Regular ultrasounds and pro-active prenatal
care can usually detect symptoms early on in a pregnancy.

MeckelGruber syndrome (MKS) is an

autosomal recessive lethal
malformation
Recently, two MKS genes, MKS1 and MKS3, have been
identified.
A study done recently has described the cellular,
sub-cellular and functional characterization of the novel
proteins, MKS1 and meckelin, encoded by these genes.[4]
The malfunction of this protein production is mainly
responsible for this lethal disorder
Thus, MeckelGruber syndrome is a ciliopathy. Other
known ciliopathies include primary ciliary dyskinesia,
BardetBiedl syndrome, polycystic kidney and
liver disease, nephronophthisis, Alstrom syndrome, and
some forms of retinal degeneration.[5] The MKS1 gene
has been explicitly identified as a ciliopathy.

Alport Syndrome
Hereditary Nephritis
The primary indicator of Alport syndrome is a family history
of chronic glomerular disease, although it may also involve
hearing or vision impairment.
This syndrome affects both men and women, but men are
more likely to experience chronic kidney disease and sensory
loss.
Alport syndrome (Hereditary Nephritis) is a
genetic disorder[1] characterized by glomerulonephritis,
endstage kidney disease, and hearing loss. [2] Alport
syndrome can also affect the eyes (lenticonus). The presence
of blood in the urine (hematuria) is almost always found in
this condition.
It was first identified in a British family by Dr. Cecil A. Alport
in 1927

Alport syndrome
Alport syndrome is caused by mutations in COL4A3,
COL4A4, and COL4A5, collagen biosynthesis genes.
Mutations in any of these genes prevent the proper
production or assembly of the type IV collagen network,
which is an important structural component of basement
membranes in the kidney, inner ear, and eye.
Basement membranes are thin, sheet-like structures that
separate and support cells in many tissues.
When mutations prevent the formation of type IV
collagen fibers, the basement membranes of the kidneys
are not able to filter waste products from the blood and
create urine normally, allowing blood and protein into the
urine. T

Alport syndrome
abnormalities of type IV collagen in kidney
basement membranes cause gradual scarring of
the kidneys, eventually leading to kidney failure in
many people with the disease.
Progression of the disease leads to basement
membrane thickening and gives a "basket-weave"
appearance from splitting of the lamina densa.
Single molecule computational studies of type IV
collagen molecules have shown changes in the
structure and nanomechanical behavior of mutated
molecules, notably leading to a bent molecular
shape with kinks.[6]

inheritance patterns that are

dependent on the genetic mutation.
In most people with Alport syndrome, the condition is inherited in an
X-linked pattern, due to mutations in the COL4A5 gene. A condition is
considered X-linked if the gene involved in the disorder is located on the
X chromosome. In males, who have only one X chromosome, one altered
copy of the COL4A5 gene is sufficient to cause severe Alport syndrome,
explaining why most affected males eventually develop kidney failure. In
females, who have two X chromosomes, a mutation in one copy of the
COL4A5 gene usually results in blood in the urine, but most affected
females do not develop kidney failure.
Alport syndrome can be inherited in an autosomal recessive pattern if
both copies of the COL4A3 or COL4A4 gene, located on chromosome 2,
have been mutated. Most often, the parents of a child with an autosomal
recessive disorder are not affected but are carriers of one copy of the
altered gene.
Past descriptions of an autosomal dominant form are now usually
categorized as other conditions,[7] though some uses of the term in
reference to the COL4A3 and COL4A4 loci have been published. [8][9]

 Men with Alport syndrome usually first show

evidence of renal insufficiency while in their
twenties and reach total kidney failure by age 40.
Women rarely have significant renal impairment,
and hearing loss may be so slight that it can be
detected only through testing with special
equipment.
Usually men can pass the disease only to their
daughters. Women can transmit the disease to
either their sons or their daughters. Treatment
focuses on controlling blood pressure to maintain
kidney function.

 As there is no known cure for the condition, treatments are

symptomatic. Patients are advised on how to manage the
complications of kidney failure, and the proteinuria that
develops is often treated with ACE inhibitors, although they
are not always used simply for the elevated blood pressure.
[12]

Once kidney failure has developed, patients are given

dialysis or can also benefit from a kidney transplant,
although this can also cause problems. The body may
reject the new kidney as it contains normal type IV
collagen, which may be recognized as foreign by the
immune system.[13]
Gene therapy as a possible treatment option has been
discussed

nephronophthisis
is characterized by fibrosis and the formation of cysts in a
specific region of the kidney. In contrast to other cystic
diseases of the kidney in which the kidneys are larger than
usual, in nephronophthisis the kidneys are small to normal in
size.

From sequencing the DNA of individuals and families with
nephronophthisis, scientists have identified thus far 8 different
genes in which mutations can cause the disease. These genes
are called NPHP1, NPHP2, NPHP3, NPHP4, NPHP5, NPHP6,
NPHP7, and NPHP8, and the proteins for which they encode
are known as the nephrocystins. Although the biological
function of these proteins is not yet known, they all localize at
least in part to an organelle in the cell called the primary cilia.

nephronophthisis

Infantile, juvenile, and adolescent forms of nephronophthisis have

been identified. Although the range of characterizations is broad,
patients typically present with polyuria (production of large
volume of urine), polydipsia (excessive liquid intake), and mild
proteinuria (the abnormal appearance of protein in the urine), and
after several months to years, end-stage kidney disease, a
condition necessitating either dialysis or a kidney transplant in
order to survive.
Approximately 10% of individuals with nephronophthisis also have
so-called "extra-renal symptoms" which can include blindness,
liver problems, severe global developmental delay or mental
retardation, and neurologic involvement in which the cerebellum is
affected.
Histology
Histologically, nephronophthisis is characterized by fibrosis and
the formation of cysts in a specific region of the kidney. In contrast
to other cystic diseases of the kidney in which the kidneys are
larger than usual, in nephronophthisis the kidneys are small to
normal in size.

Nephronophthisis is a
ciliopathy
Recent findings in genetic research have
suggested that a large number of
genetic disorders, both genetic syndromes and
genetic diseases, that were not previously
identified in the medical literature as related, may
be, in fact, highly related in the genetypical root
cause of the widely-varying, phenotypicallyobserved disorders.
Thus, Nephronophthisis is a ciliopathy. Other
known ciliopathies include
primary ciliary dyskinesia, Bardet-Biedl syndrome,
polycystic kidney and liver disease,
Alstrom syndrome, Meckel-Gruber syndrome and
some forms of retinal degeneration

Dent's disease
(or Dent disease) is a rare X-linked recessive
inherited condition that affects the
proximal renal tubules [1] of the kidney. It is one cause
of Fanconi syndrome, and is characterized by tubular
proteinuria, hypercalciuria, calcium nephrolithiasis,
nephrocalcinosis and chronic renal failure.
"Dent's disease" is often used to describe an entire
group of familial disorders, including X-linked
recessive nephrolithiasis with renal failure, X-linked
recessive hypophosphataemic rickets, and both
Japanese and idiopathic low molecular weight
proteinuria.[2]

Dent's disease
was first described by Dent, C. E. and Friedman, M in 1964
when they reported 2 unrelated British boys with rickets
associated with renal tubular damage characterized by
hypercalciuria, hyperphosphaturia, proteinuria, and
aminoaciduria.[3] This is a genetic disorder caused by the
genetic mutations in the renal chloride channel CLCN5
which encodes a kidney-specific voltage gated
chloride channel and a 746 amino acid protein (CLC-5), with
12 to 13 transmembrane domains; it manifests itself
through low molecular weight proteinuria, hypercalciuria,
aminoaciduria and hypophosphataemia. Because of its
rather rare occurrence, Dent's disease is often diagnosed as
idiopathic hypercalciuria (IH), i.e. excess calcium in urine
with undetermined causes.

Dent disease 1 & 2

Dent disease 1
Dent's disease is a X-linked recessive disorder. The males are prone to
manifesting symptoms in early adulthood with symptoms of calculi,
rickets or even with renal failure in more severe cases.
In humans, gene CLCN5 is located on chromosome Xp11.22 and has a
2238-bp coding sequence that consists of 11 exons that span 25 to 30
kb of genomic DNA and encode a 746 amino acid protein. [4] CLCN5
belongs to the family of voltage-gated chloride channel genes (CLCN1CLCN7, and CLCKa and CLCKb) that have approximately 12
transmembrane domains. These chloride channels have an important
role in the control of membrane excitability, transepithelial transport,
and possibly cell volume.[5]
The mechanisms by which CLC-5 dysfunction results in hypercalciuria
and the other features of Dent's disease remain to be elucidated. The
identification of additional CLCN5 mutations may help in these studies,
and we have pursued such studies in patients with Dent's disease. [6]

Dent's disease often produces

symptoms of:
Extreme thirst combined with dehydration which leads to frequent
urination
Nephrolithiasis (kidney stones)
Hypercalciuria (high urine calcium - >300 mg/d or >4 mg/kg per d) with
normal levels blood/serum calcium)
Dent's disease may also be associated with:
Aminoaciduria (amino acids in urine)
Phosphaturia (phosphate in urine)
Glycosuria (glucose in urine)
Kaliuresis (potassium in urine)
Hyperuricosuria (excessive amounts of uric acid in the urine.)
Impaired urinary acidification
Rickets
In a very large study of patients with Dent's disease, 9 out of 15 men,
and 1 out of 10 women suffered end-stage renal failure by the age of 47

Dent's disease
As of today, there is no agreed-upon treatment of Dent's disease and no therapy
has been formally accepted. Most treatment measures are mostly supportive in
nature and they include:
Thiazide diuretics (i.e. Hydrochlorothiazide) which have been used with success in
reducing the calcium output in urine, but they are also known to cause
hypokalemia.
In rats with diabetes insipidus thiazide diuretics inhibit the NaCl co-transporter in the renal
distal convoluted tubule leading indirectly to less water and solutes being delivered to the
distal tubule.[10]

Amiloride which also increases distal tubular calcium reabsorption and has been
used as a therapy for idiopathic hypercalciuria.
A combination of 25 mg of chlorthalidone plus 5 mg of amiloride daily led to a substantial
reduction in urine calcium in Dent's patients, however urine pH was "significantly higher in
patients with Dents disease than in those with idiopathic hypercalciuria (P < 0.03), and
supersaturation for uric acid was consequently lower (P < 0.03)."[11]

For patients with osteomalacia, Vitamin D or derivatives have been employed,

apparently with success.
Some lab tests on mice with CLC-5 related tubular damage showed that a high
citrate diet preserved renal function and delayed progress of renal disease

Gitelman syndrome
is a rare inherited defect in the
distal convoluted tubule of the kidneys. It
causes the kidneys to pass sodium,
magnesium, chloride, and potassium into
the urine, rather than allowing it to be
resorbed into the bloodstream.
Gitelman syndrome is not to be confused
with Bartter syndrome, which is a rare
inherited defect in the
thick ascending limb of the loop of Henle.

Gitelman syndrome
Gitelman syndrome has an autosomal recessive
pattern of inheritance.
Gitelman's syndrome is linked to inactivating
mutations in the SLC12A3 gene resulting in a loss of
function of the encoded thiazide-sensitive
sodium-chloride co-transporter (NCCT). This cell
membrane protein participates in the control of ion
homeostasis at the distal convoluted tubule portion
of the nephron.
Gitelman's syndrome is an autosomal-recessive
disorder: one defective gene has to be inherited
from each parent.

Gitelman's syndrome
People suffering from Gitelman's syndrome present symptoms which
are identical to those of patients who are on thiazide diuretics[1]
Clinical symptoms for this disease are hypochloremic
metabolic alkalosis, hypokalemia, and hypocalciuria. Hypomagnesemia
is present in many but not all cases. In contrast to patients with
Gordon's syndrome, those suffering from Gitelman's syndrome are
generally normotensive. Carriers of Gitelman's syndrome-linked
mutations are often asymptomatic while some complain of mild
muscular cramps or weakness expressed as fatigue or irritability. More
severe symptoms such as tetany and paralysis have however also been
reported. Phenotypic variations observed among patients probably
result from differences in their genetic background and may depend on
which particular amino acid in the NCCT protein has been mutated.
See Naesens et al. for a recent review.[2]
Eponym
It is named for Hillel Gitelman

Papillorenal syndrome,
also called Renal-coloboma
syndrome or isolated renal
hypoplasia,[1] is an autosomal
dominant[2] genetic disorder marked
by underdevelopment (hypoplasia) of
the kidney and colobomas of the
optic nerve

Papillorenal syndrome
is an autosomal dominant disorder that
results from a mutation of one copy of the
PAX2 gene, located on chromosome
10q24.3-q25.1.[2][3] The gene is
important in the development of both the
eye and the kidney.
Autosomal dominant inheritance indicates
that the gene responsible for the disorder
is located on an autosome (chromosome
10 is an autosome), and only one
defective copy of the gene is sufficient to
cause the disorder, when inherited from a
parent who has the disorder

Potter's syndrome,

Potter sequence (also known as Potter's sequence or

Oligohydramnios sequence) is the atypical physical appearance
of a fetus or neonate due to oligohydramnios experienced in the
womb.[1] Oligohydramnios is the decrease in amniotic fluid
volume sufficient to cause in morphogenesis of the fetus.
Oligohydramnios is the causative agent of Potter sequence, but
there are many things that can lead to oligohydramnios.
It can be caused by renal diseases such as bilateral renal agenesis
(BRA), atresia of the ureter or urethra causing obstruction of the
urinary tract, polycystic or multicystic kidney diseases, renal
hypoplasia, , uteroplacental insufficiency from maternal
hypertension or toxemia.
Potter's sequence is known in the medical field as clubbed feet,
pulmonary hypoplasia and cranial anomalies related to the
oligohydramnios.
The term Potter sequence was initially intended to only refer to
cases caused by BRA,[citation needed] however, it has been
mistakenly used by many clinicians and researchers to refer to any
case that presents with oligohydramnios or anhydramnios
regardless of the source of the loss of amniotic fluid.[

Bilateral renal agenesis

(BRA)

was first recognized as a defect of human fetal development in

1671 by Wolfstrigel
In 1946 when Edith Potter (b.1901 - d.1993) described a series of
20 cases with absent kidneys, noting the characteristic
appearance of the head and lungs.[3][4]
Up until this time the condition itself was considered to be
extremely rare. However, in part to Potter's work it has come to
light that the condition presents far more frequently than
previously reported. Potter analyzed approximately 5000 autopsy
cases performed on fetuses and newborn infants over a period of
ten years and found that 20 of these infants presented with BRA,
all of which had distinctive facial characteristics.
These facial characteristics have subsequently be termed as being
known as Potter facies. From her analysis she was able to deduce
the sequence of events that leads to what is now known as Potter
sequence.
Potter went on to become a pioneer in the field of human renal
development and her contributions are still employed and
appreciated by clinicians and researchers to this day.

bilateral renal agenesis

(BRA)
meaning that kidneys do not develop
(malformation of the ureteric bud).
True BRA also presents with bilateral agenesis of
the ureters. After the creation of the
nomenclature system for this sequence,
BRA was recognized as possibly being an extreme
variation of Potter sequence II. However, some
clinicians and researchers still use the term
classic Potter sequence so as to emphasize that
they are specifically referring to cases of BRA and
not another form.

Type I
Type I is due to
autosomal recessive polycystic kidne
y
disease (ARPKD), which occurs at a
frequency of approximately one in
16,000 infants. The kidneys of the
fetus/neonate will be enlarged, have
many small cysts filled with fluid and
will fail to produce an adequate
volume of fetal urine. The liver and
pancreas of the fetus may also show
fibrosis and/or a cystic change.

Type II
Type II is usually due to renal agenesis,[5] which
can also fall under the category known as
hereditary urogenital adysplasia or hereditary
renal adysplasia (HRA). This is characterized by
the complete agenesis or absence of one kidney
and the remaining solitary kidney being small and
malformed. Bilateral renal agenesis is believed to
be the most extreme phenotypic variation of HRA.
However, BRA is often referred to as classic Potter
sequence, as it was this particular phenotype of
neonates and fetuses that Potter originally
reported in her 1946 manuscripts when
characterizing this birth defect.

Type III
Type III is due to
Autosomal dominant polycystic kidney
disease (ADPKD) linked to mutations in the
genes PKD1 and PKD2. While ADPKD is
considered to be an adult-onset polycytic
kidney disease, it can also present in the
fetus and neonate in rare cases. Like
ARPKD, ADPKD can also present with
hepatic cysts and an enlarged spleen. An
increased prevalence of vascular disease
is also observed in these cases of ADPKD.

Classic Potter
Classic Potter sequence occurs when the
developing fetus has bilateral renal agenesis,
which also presents with agenesis of the ureters.
BRA has been estimated to occur at a frequency
of approximately 1:4000 to 1:8000 fetuses and
neonates.
However, recent analysis has estimated that the
condition may occur at a much greater frequency.
The condition has been reported to occur twice as
common in males as in females, suggesting that
certain genes of the Y chromosome may act as
modifiers. However, no candidate genes on the
Y chromosome have yet been identified.

BRA
BRA appears to have a predominantly genetic etiology and many
cases represent the most severe manifestation of an autosomal
dominant condition with incomplete penetrance and variable
expressivity.
There are several genetic pathways that could result in this
condition. To date, few of these pathways or candidate genes have
been considered or analyzed regarding BRA.
The majority of possible candidate genetic pathways are autosomal
recessive in nature and do not coincide with the frequency or
penetrance at which BRA occurs in the human population.
Additionally, candidate genetic pathways would be expected to
involve genes expressed in the developing urogenital system (UGS).
Often, these same genes and/or pathways of interacting genes are
also expressed in the developing UGS as well as the
central nervous system (CNS), gut, lung, limbs, and eyes