ALPORT’S SYNDROME

Alport syndrome is a disease that damages the tiny blood vessels in the kidneys. It can lead to kidney
disease and kidney failure. It can also cause hearing loss and problems within the eyes. Alport syndrome
causes damage to the kidneys by attacking the glomeruli. Glomeruli are the tiny filtering units inside the
kidneys.

Causes of Alport Syndrome

Alport syndrome is an inherited disease, which means it is passed down through families. It is caused by
changes in the genes (mutations) to a protein called collagen. Collagen is important to the normal
structure and function of the kidneys. Changes to collagen can also cause problems with the eyes and
ears. That’s because collagen helps maintain healthy tissue in the eyes and ears.

Genetic types of Alport Syndrome

There are three genetic types of Alport syndrome.

 X-linked Alport syndrome (XLAS)

 Autosomal recessive Alport syndrome (ARAS)
 Autosomal dominant Alport syndrome (ADAS)

X-linked Alport syndrome: X-linked (related to the X chromosome) is the most common form of Alport
Syndrome. About 80% of the people with this disease have the X-linked type. Boys with this type are
severely affected and always develop kidney failure sometime in their lives. Girls with this type usually
have milder symptoms than boys, but they can develop kidney failure.
Autosomal recessive Alport syndrome (ARAS): This is when both parents carry the abnormal gene and
both parents pass the abnormal gene to the child. Both copies of the abnormal gene are needed to cause
the autosomal recessive type of Alport Syndrome.
Autosomal dominant Alport syndrome (ADAS): This happens when one parent has the disease and passes
the abnormal gene to the child. In other words, only one copy of the abnormal gene is needed to cause the
disease.

Signs and symptoms of Alport Syndrome

With all types of Alport syndrome the kidneys are affected. The tiny blood vessels in the
glomeruli of the kidneys are damaged and cannot filter the wastes and extra fluid in the body.
Many people with Alport syndrome also have hearing problems and abnormalities with their
eyes.
Other signs and symptoms may include:

 Blood in the urine (hematuria), the most common and earliest sign of Alport syndrome
 Protein in the urine (proteinuria)
 High blood pressure (hypertension)
 Swelling in the legs, ankle, feet and around the eyes (called edema)
These signs and symptoms may differ, based on age, gender and inherited type of Alport
syndrome. For example, hearing and vision problems tend to be more common in males than
females and high blood pressure is usually found later in life.
Alport syndrome diagnose
The healthcare provider will have to watch the signs, symptoms, and look at the family history to know if
they have Alport syndrome. The following tests or exams may be done to help the healthcare provider
make a diagnosis:

 Urine test: A urine test will help find protein and blood in the urine.
 Blood test: A blood test will help find levels of protein, and wastes in your blood.
 Glomerular filtration rate (GFR): A blood test will be done to know how well your kidneys are
filtering the wastes from the body.
 Kidney biopsy: In this test, a tiny piece of the kidney is removed with a special needle, and
looked at under a microscope.
 Hearing test: A hearing test will be done to see if yje hearing has been affected.
 Vision test: A vision test will be done to see if the vision has been affected.

 Genetic test: This can help confirm the diagnosis and determine the genetic type of Alport
syndrome they may have.

Treatment of Alport Syndrome

Currently, there is no specific treatment for Alport syndrome. The goal is to treat the symptoms and help
slow the progression of kidney disease. This may include:

 ACE inhibitor or ARB medicines (medications to control high blood pressure)

 Diuretics (water pills)
 Limit sodium (salt) in your diet

If they are approaching kidney disease because of Alport syndrome, a kidney transplantation is usually
very successful in people with Alport syndrome and is considered the best treatment when kidney failure
is approaching.

AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE (ARPKD)

Autosomal recessive polycystic kidney disease (ARPKD) is the recessive form of polycystic kidney
disease. It is associated with a group of congenital fibrocystic syndromes. Mutations in
the PKHD1 (chromosomal locus 6p12.2) cause ARPKD.

Signs and symptoms

Symptoms and signs include abdominal discomfort, polyuria, polydipsia, incidental discovery
of hypertension, abdominal mass. The classic presentation for ARPKD is systemic hypertension with
progression to end-stage renal disease (ESRD) by the age of 15. In a typical presentation, a small number
of ARPKD sufferers live to adulthood with some kidney function; but with significant deterioration in
liver function. This outcome is postulated to result from expression of the polycystic kidney and hepatic
disease gene PKHD1, which is located on chromosome 6p. In severe cases, a fetus will present
with oligohydramnios and as a result, may present with Potter sequence.

Genetics
ARPKD is a significant hereditary renal disease in that appears in childhood. The prevalence is estimated
to be of 1 in 20,000 live births. With a reported carrier frequency of up to 1:70. The single gene mutation
called ‘’PKHD1’’ is fully responsible for the disease presentation of ARPKD. This PKHD1 is located on
the human chromosome region 6p21.1-6p12.2. It is also one of the largest genes in the genome as it
occupies approximately 450 kb of DNA, and contains at least 86 exons.[10]
It is capable of producing multiple alternatively spliced transcripts. The largest known transcript
encodes fibrocystin /polyductin (FPC), which is a large receptor-like integral membrane protein of 4074
amino acids. The structure of the FPC consist of a single transmembrane, a large N-terminal extracellular
region, and a short intracellular cytoplasmic domain. The FPC protein is found on the primary cilia of
epithelia cells of cortical and medullary collecting ducts and cholangiocytes of bile ducts, and show
similarity to polycystins and several other ciliopathy proteins.[10] FPC is also found to be expressed on the
basal body and plasma membrane. It is presumed that the large extracellular domain of FPC binds to a
ligand(s) that is yet unknown and that is also involved in cell-cell and cell-matrix interactions.
It is known that FPC interacts with ADPKD protein PC2 and may also participate in this regulation
pathway of the mechanosensory function of the primary cilia, calcium signaling, and PCP. This is
suggesting a common mechanism underlying cystogenesis between ADPKD and ARPKD. The FPC
protein is also found on the centrosomes and mitotic spindle and may regulate centrosome duplication and
mitotic spindle assembly during cell division. There have been a large number of various single gene
mutations found throughout PKHD1 and are unique to individual families. Most of the patients
are compound heterozygotes for PKHD1 mutations. Patients with two nonsense mutations appear to have
an earlier onset of the disease.

Diagnosis
Ultrasonography is the primary method to evaluate autosomal recessive polycystic kidney disease,
particularly in the perinatal and neonatal.
Differential diagnosis
The DDx of this condition is the following:

 Glomerulocystic kidney disease

 Autosomal dominant polycystic kidney disease
 Diffuse cystic dysplasia

Treatment
The treatment options for autosomal recessive polycystic kidney disease, given there is no current cure,
are:

 Medications for hypertension

 Medications and/or surgery for pain
 Antibiotics for infection
 Kidney transplantation(in serious cases)
 Dialysis (if renal failure)

AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent, potentially
lethal, monogenic human disorder. It is associated with large interfamilial and intrafamilial variability,
which can be explained to a large extent by its genetic heterogeneity and modifier genes. It is also the
most common of the inherited cystic kidney diseases — a group of disorders with related but distinct
pathogenesis, characterized by the development of renal cysts and various extrarenal manifestations,
which in case of ADPKD include cysts in other organs, such as the liver, seminal vesicles, pancreas,
and arachnoid membrane, as well as other abnormalities, such as
intracranial aneurysms and dolichoectasias, aortic root dilatation and aneurysms, mitral valve prolapse,
and abdominal wall hernias. Over 50% of patients with ADPKD eventually develop end stage kidney
disease and require dialysis or kidney transplantation. ADPKD is estimated to affect at least 1 in every
1000 individuals worldwide, making this disease the most common inherited kidney disorder with a
diagnosed prevalence of 1:2000 and incidence of 1:3000-1:8000 in a global scale.

Signs and symptoms

 Acute loin pain

 Haematuria
 Ballotable kidneys
 Sub arachnoid hemorrhage(berry aneurysm)
 Hypertension
 Associated liver cyst
 Uremia due to renal failure
 Anemia due to CKD
 Increase RBC or erythropoeitin secretion

Pathophysiology
In many patients with ADPKD, kidney dysfunction is not clinically apparent until forty or fifty years of
life. There is, however, an increasing body of evidence that suggests the formation of renal cysts starts in
utero. Cysts initially form as small dilations in renal tubules, which then expand to form fluid-filled
cavities of different sizes. Factors suggested to lead to cystogenesis include a germline mutation in one of
the polycystin gene alleles, a somatic second hit that leads to the loss of the normal allele, and a third hit,
which can be anything that triggers cell proliferation, leading to the dilation of the tubules. In the
progression of the disease, continued dilation of the tubules through increased cell proliferation, fluid
secretion, and separation from the parental tubule lead to the formation of cysts.
ADPKD, together with many other diseases that present with renal cysts, can be classified into a family of
diseases known as ciliopathies. Epithelial cells of the renal tubules, including all the segments of the
nephron and the collecting ducts (with the exception of intercalated cells) show the presence of a single
primary apical cilium. Polycystin-1, the protein encoded by the PKD1 gene, is present on these cilia and
is thought to sense the flow with its large extracellular domains, activating the calcium channels
associated with polycystin-2, the product of gene PKD2, as a result of the genetic setting of ADPKD as
explained in the genetics sub-section below.
Epithelial cell proliferation and fluid secretion that lead to cystogenesis are two hallmark features in
ADPKD. During the early stages of cystogenesis, cysts are attached to their parental renal tubules and a
derivative of the glomerular filtrate enters the cysts. Once these cysts expand to approximately 2 mm in
diameter, the cyst closes off from its parental tubule and after that fluid can only enter the cysts through
transepithelial secretion, which in turn is suggested to increase due to secondary effects from an increased
intracellular concentrations of cyclic AMP (cAMP).
Diagnosis
Usually, the diagnosis of ADPKD is initially performed by renal imaging using ultrasound, CT scan,
or MRI. However, molecular diagnostics can be necessary in the following situations: 1- when a definite
diagnosis is required in young individuals, such as a potential living related donor in an affected family
with equivocal imaging data; 2- in patients with a negative family history of ADPKD, because of
potential phenotypic overlap with several other kidney cystic diseases; 3- in families affected by early-
onset polycystic kidney disease, since in this cases hypomorphic alleles and/or oligogenic inheritance can
be involved; and 4- in patients requesting genetic counseling, especially in couples wishing a pre-
implantation genetic diagnosis.
The findings of large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk
for ADPKD are diagnostic. In the absence of a family history of ADPKD, the presence of bilateral renal
enlargement and cysts, with or without the presence of hepatic cysts, and the absence of other
manifestations suggestive of a different renal cystic disease provide presumptive, but not definite,
evidence for the diagnosis. In some cases, intracranial aneurysms can be an associated sign of ADPKD,
and screening can be recommended for patients with a family history of intracranial aneurysm.
Molecular genetic testing by linkage analysis or direct mutation screening is clinically available; however,
genetic heterogeneity is a significant complication to molecular genetic testing. Sometimes a relatively
large number of affected family members need to be tested in order to establish which one of the two
possible genes is responsible within each family. The large size and complexity
of PKD1 and PKD2 genes, as well as marked allelic heterogeneity, present obstacles to molecular testing
by direct DNA analysis. The sensitivity of testing is nearly 100% for all patients with ADPKD who are
age 30 years or older and for younger patients with PKD1 mutations; these criteria are only 67% sensitive
for patients with PKD2 mutations who are younger than age 30 years.

Treatment
Currently, the only clinical/pharmacological treatment available for ADPKD consists in reducing the
speed in gain of total kidney volume (TKV) with aquaretics (i.e. tolvaptan), which can alleviate pain
while giving the patients a better quality of life for over a mean of 3 years. After this period, patients can
restart gaining TKV at pre-treatment rates and may eventually have to go through dialysis and kidney
transplant. Palliative treatment modalities involve symptomatic medications (non-opioid and opioid
analgesics) for abdominal/retroperitoneal pain. Before the advent of aquaretic medication, the only option
for analgesic-resistant pain were simple or complex surgical procedures (i.e. renal cyst aspiration, cyst
decortication, renal denervation and nephrectomy), which can result in complications inherent to surgery.
Aquaretic medication
Tolvaptan, an aquaretic drug, is a vasopressin receptor 2 (V2) antagonist. Pre-clinical studies had
suggested that the molecule cAMPcould be involved in the enlargement of ADPKD cysts,
Analgesic medication
Chronic pain in patients with ADPKD is often refractory to conservative, non-invasive treatments,
but non-opioid analgesics and conservative interventions can be first used before opioid analgesics are
considered; if pain continues, then surgical interventions can target renal or hepatic cysts in order to
directly address the cause of pain, with surgical options including renal cyst decortication,
renal denervation, and nephrectomy.
Renal cyst aspiration
Aspiration with ethanol sclerotherapy can be performed for the treatment of symptomatic simple renal
cysts, but can be impractical in advanced patients with multiple cysts. The procedure itself consists in the
percutaneous insertion of a needle into the identified cyst, under ultrasound guidance, with subsequent
draining the contained liquid; the sclerotherapy is used to avoid liquid reaccumulation that can occur in
the cyst, which can result in symptom recurrence.
Laparoscopic cyst decortication
Laparoscopic cyst decortication (also referred to as marsupialization) consists in the removal of one or
more kidney cysts through laparoscopic surgery, during which cysts are punctured, and the outer wall of
the larger cysts is excised with care not to incise the renal parenchyma. This procedure can be useful for
pain relief in patients with ADPKD, and is usually indicated after earlier cyst aspiration has confirmed
that the cyst to be decorticated is responsible for pain. Non-randomised controlled trials conducted in the
90s showed that patients with symptomatic simple renal cysts who had recurrence of symptoms after
initial response to simple aspiration could be safely submitted to cyst decortication, with a mean pain-free
life between 17 and 24 months after surgery. Laparoscopic decortication presents a 5% recurrence rate of
renal cysts compared to an 82% recurrence rate obtained with sclerotherapy.
Nephrectomy
Many ADPKD patients suffer symptomatic sequelae in consequence of the disease, such as
cyst hemorrhage, flank pain, recurrent infections, nephrolithiasis, and symptoms of mass effect (i.e.,
early satiety, nausea and vomiting, and abdominal discomfort), from their enlarged kidneys. In such
cases, nephrectomy can be required due to intractable symptoms or when, in the course of preparing
for renal transplantation, the native kidneys are found to impinge upon the true pelvis and preclude the
placement of a donor allograft Additionally, native nephrectomy may be undertaken in the presence of
suspected malignancy, as renal cell carcinoma (RCC) is 2 to 3 times more likely in the ADPKD
population in end stage renal disease (ESRD) than in the ESRD patients without ADPKD. Although the
indications for nephrectomy in ADPKD may be related to kidney size, the decision to proceed with native
nephrectomy is often undertaken on an individual basis, without specific reference to kidney size
measurements.
Dialysis
Two modalities of dialysis can be used in the treatment of ADPKD patients: peritoneal
dialysis and hemodialysis. Peritoneal dialysis has usually been contra-indicated in ADPKD patients with
large kidney and liver volumes, due to expected physical difficulties in the procedure and possible
complications.
Kidney transplant
It is accepted that kidney transplantation is the preferred treatment for ADPKD patients with end-stage
renal disease (ESRD).

HORSE SHOE KIDNEY

Horseshoe kidney, also known as ren arcuatus (in Latin), renal fusion or super kidney, is a congenital
disorder affecting about 1 in 600 people, more common in men.
In this disorder, the patient's kidneys fuse together to form a horseshoe-shape during development in the
womb. The fused part is the isthmus of the horseshoe kidney.
Fusion abnormalities of the kidney can be categorized into two groups: horseshoe kidney and crossed
fused ectopia. The 'horseshoe kidney' is the most common renal fusion anomaly.

Signs and symptoms

In patients with this condition, the central portion of the kidney may be found just inferior to the inferior
mesenteric artery because the normal embryologic ascent of the kidneys is arrested by its presence in
people with central fusion of the kidneys. Horseshoe kidney is often asymptomatic, though persons
affected by this condition may experience nausea, abdominal discomfort, kidney stones and urinary tract
infections at greater frequency than those without renal fusion. There is currently no treatment for renal
fusion other than symptomatic treatment.

Imaging findings:

 The two kidneys on opposite sides of the body with the lower poles fused in midline. Midline or
symmetrical fusion (90% of cases).
 May be missed on US, therefore pay careful attention to identification of lower poles of kidneys.
 Renal long axis medially orientated,
 Lower poles with curved configuration, elongation and poorly defined
 Isthmus crosses midline anterior to spine and great vessels.
 US for diagnosis in utero
 IVP followed by CT or scintigraphy for pre-operative assessment
Variant arterial supply:

 Bilateral renal arteries,

 Inferior mesenteric artery,
 Arteries arising from aorta or common iliac, internal iliac, external iliac or inferior mesenteric
arteries.
The lower poles of these kidneys fuse in the midline anterior to the aorta and spine. The isthmus is
usually located at L4/5 level between the aorta and IMA.
Nuclear medicine (DMSA) scan confirms horseshoe kidney with fusion of both renal lower poles.
Associated conditions
While most cases of horseshoe kidneys are asymptomatic and discovered upon autopsy, the condition
may increase the risk for:

 Kidney obstruction – abnormal placement of ureter may lead to obstruction and dilation of the
kidney.
 Kidney infections – associated with vesicoureteral reflux.
 Kidney stones – deviant orientation of kidneys combined with slow urine flow and kidney
obstruction may lead to kidney stones.
 Turner Syndrome - a missing or incomplete X chromosome on the 23rd pair
 Kidney cancer – increased risk of renal cancer, especially Wilms' tumor, transitional cell carcinoma,
and an occasional case report of carcinoid tumor. Despite increased risk, the overall risk is still
relatively low.
The prevalence of horseshoe kidneys in females with Turner syndrome is about 15%.
It can be associated with trisomy 18.
It can be associated with venous anomalies like left sided IVC 9

Diagnosis and Treatment

Doctors usually don’t diagnose horseshoe kidney before birth. Since its symptoms are similar to those of other
health problems, it’s important to see the child’s doctor to make sure they get the correct diagnosis.
The doctor will ask about the child’s symptoms and health history, and she’ll do a physical exam. She may
also suggest other tests, such as:

 Blood tests to see how well the kidneys are working

 Urine tests, which check for signs of infection
 Kidney ultrasound, a test that uses sound waves to make a picture of the organ. It can help the doctor
see any kidney stones, cysts, or tumors.
 Intravenous pyelogram (IVP) orvoiding cystourethrogram (VCUG), special X-rays that show how
urine flows inside the body

There’s no cure for horseshoe kidney. Once the kidneys fuse in a horseshoe shape, they stay that way. But can
can treat some of the problems the condition can cause. For instance, the child may take antibiotics for an
infection or have surgery for kidney stones.
If the child has no symptoms, he may not need any treatment.